Mouse Genome Informatics
cn1
    Vegfatm2Gne/Vegfatm2Gne
Tg(SFTPC-rtTA)5Jaw/0
Tg(tetO-cre)1Jaw/0

involves: 129 * 129/Sv * C57BL/6
Key:
phenotype observed in females WTSI Wellcome Trust Sanger Institute
phenotype observed in males EuPh Europhenome
N normal phenotype
mortality/aging
• newborn mice exposed to doxycycline from E6.5 develop respiratory distress and die within 1-2 hrs of birth

respiratory system
• at E18.5, doxycycline-exposed mice display an almost complete absence of pulmonary capillaries associated with defective primary septation during distal lung morphogenesis
• at E18.5, lung saccular walls without capillaries exhibit no septae while septae containing a residual (single) capillary or disorganized capillaries are malformed and show abnormal shapes with an expanded mesenchyme
• at E18.5, doxycycline-exposed mice exhibit significantly reduced pulmonary endothelial cell development relative to controls
• at birth, doxycycline-exposed mice display white lungs, indicating a lack of pulmonary circulation
• mice exposed to doxycycline from E6.5 display defective distal lung saccular development due to reduced primary septation; first seen at E16.5 when terminal tubules appear more dilated
• defective distal airspace morphogenesis is also noted when mice are exposed to doxycycline from E14.5 to birth
• impaired primary septation is likely due to reduced hepatocyte growth factor (Hgf) expression
• at E18.5, doxycycline-exposed mice display a significant reduction in proliferating (BrdU+) lung mesenchymal cells relative to controls
• at E18.5, doxycycline-exposed mice display significantly dilated distal airspaces with fewer subdivisions by primary septae than controls
• at E18.5, doxycycline-exposed mice display a mosaic pattern of normal and abnormal septae that is dependent on the residual capillary structures
• at birth, ventilation of doxycycline-exposed lungs results in marked dilation of terminal airspaces and thinning of saccular walls
• at E18.5, doxycycline-exposed mice display a 65% reduction in proliferating (BrdU+) lung epithelial cells relative to controls
• however, epithelial cell survival and proximal-distal patterning of epithelial cell differentiation remain normal
• at E16.5 and E17.5, doxycycline-exposed mice display abnormal distal acini and more dilated distal tubules than controls
• at birth, doxycycline-exposed mice display white lungs
• newborn mice exposed to doxycycline from E6.5 develop respiratory distress and die within 1-2 hrs of birth

cardiovascular system
• at E18.5, doxycycline-exposed mice display an almost complete absence of pulmonary capillaries associated with defective primary septation during distal lung morphogenesis
• at E18.5, lung saccular walls without capillaries exhibit no septae while septae containing a residual (single) capillary or disorganized capillaries are malformed and show abnormal shapes with an expanded mesenchyme
• at E18.5, doxycycline-exposed mice exhibit significantly reduced pulmonary endothelial cell development relative to controls
• at E18.5, doxycycline-exposed mice display significantly reduced pulmonary capillary angiogenesis associated with defective primary septation during distal lung morphogenesis
• at birth, doxycycline-exposed mice display white lungs, indicating a lack of pulmonary circulation

cellular
• at E18.5, doxycycline-exposed mice display a significant reduction in proliferating (BrdU+) lung mesenchymal cells relative to controls


Mouse Genome Informatics
cn2
    Vegfatm2Gne/Vegfa+
Tg(SFTPC-rtTA)5Jaw/0
Tg(tetO-cre)1Jaw/0

involves: 129 * 129/Sv * C57BL/6
Key:
phenotype observed in females WTSI Wellcome Trust Sanger Institute
phenotype observed in males EuPh Europhenome
N normal phenotype
respiratory system
• at E18.5, doxycycline-exposed mice exhibit a reduction in pulmonary endothelial cell development that is intermediate between those of wild-type controls and those carrying two Vegfatm2Gne alleles
• newborn mice exposed to doxycycline from E6.5 display pale lungs, indicating reduced pulmonary circulation
• mice exposed to doxycycline from E6.5 display defective distal lung saccular development due to moderately reduced primary septation
• at E18.5, doxycycline-exposed mice display dilated distal airspaces of a size that is intermediate between those of wild-type controls and those carrying two Vegfatm2Gne alleles
• the mean linear intercept, a reflection of airspace size and hence an indirect measure of septation incidence, is inversely related to the Vegfa gene dosage
• newborn mice exposed to doxycycline from E6.5 display pale lungs

cardiovascular system
• at E18.5, doxycycline-exposed mice exhibit a reduction in pulmonary endothelial cell development that is intermediate between those of wild-type controls and those carrying two Vegfatm2Gne alleles
• newborn mice exposed to doxycycline from E6.5 display pale lungs, indicating reduced pulmonary circulation


Mouse Genome Informatics
cn3
    Foxa2tm1Khk/Foxa2tm1Khk
Tg(SFTPC-rtTA)5Jaw/0
Tg(tetO-cre)1Jaw/0

involves: 129 * 129P2/OlaHsd * C57BL/6
Key:
phenotype observed in females WTSI Wellcome Trust Sanger Institute
phenotype observed in males EuPh Europhenome
N normal phenotype
mortality/aging
• most mice treated with doxycycline from E0 die on P1
• 50% of mice treated with doxycycline from E0 through P16 died within 30 days of birth (J:88601)
• only 46% of mice treated with doxycycline from E0 survive to P5 (J:93473)

hematopoietic system
• observed in bronchoalveolar lavage from mice treated with doxycycline from E0 through P16
• observed in bronchoalveolar lavage from mice treated with doxycycline from E0 through P16

immune system
• observed in bronchoalveolar lavage from mice treated with doxycycline from E0 through P16
• observed in bronchoalveolar lavage from mice treated with doxycycline from E0 through P16

respiratory system
• mice treated with doxycycline from E0 and found to be in distress or moribund on P1 display pulmonary congestion
• impaired alveogenesis marked by fewer peripheral lung saccules and decreased alveolar septation; apparent at 3 days of age in mice treated with doxycycline from E0 through P16 (J:88601)
• at E18.5, mice treated with doxycycline from E0 display immature peripheral lung saccules, resembling those normally seen at E16-E17
• at E18.5, squamous type I cells are missing, alveolar walls are thickened and lined by immature cuboidal type II cells, cytoplasmic glycogen is dispersed, and apical microvilli are absent
• however, no evidence of capillary leakage or endothelial cell abnormalities are observed
• at E18.5, no squamous type I cells are observed in mice treated with doxycycline from E0
• at E18.5, mice treated with doxycycline from E0 show absence of lamellar bodies in alveolar type II cells
• at E18.5, mice treated with doxycycline from E0 show thickened alveolar walls lined by immature cuboidal type II cells
• increased airspace in mice prenatally treated with doxycycline
• postnatal treatment with doxycycline also resulted in increased airspace but to a lesser extent
• normal prenatal lung morphogenesis
• goblet cell hyperplasia, associated with the accumulation of both neutral and acidic mucins, observed in mice treated with doxycycline from E0 through P16
• ~50% of mice treated with doxycycline from E0 develop severe respiratory distress within 2-3 hrs of birth
• at E18.5, the fractional content of phosphatidylcholine (PC) and saturated PC are markdely reduced, whereas that of phosphatidylethanolamine, sphingomyelin, and phosphatidylserine is increased in the lungs of mice treated with doxycycline from E0
• SP-A, SP-B, and SP-C mRNAs are significantly decreased at E18.5
• the active SP-B peptide is markedly decreased in lung homogenates prior to birth
• SP-D mRNAs are significantly increased at E18.5
• at E18.5, no secreted surfactant is detected in the air spaces of mice treated with doxycycline from E0
• mice treated with doxycycline from E0 and found to be in distress or moribund on P1 display focal or extensive atelectasis
• mice treated with doxycycline from E0 and found to be in distress or moribund on P1 display hyaline membrane formation

homeostasis/metabolism
• ~50% of mice treated with doxycycline from E0 display cyanosis

behavior/neurological
• newborn mice are frequently cannibalized by the mother (J:93473)

cardiovascular system
• mice treated with doxycycline from E0 and found to be in distress or moribund on P1 display pulmonary congestion


Mouse Genome Informatics
cn4
    Stat3tm2Aki/Stat3tm2Aki
Tg(SFTPC-rtTA)5Jaw/0
Tg(tetO-cre)1Jaw/0

involves: 129 * 129P2/OlaHsd * C57BL/6
Key:
phenotype observed in females WTSI Wellcome Trust Sanger Institute
phenotype observed in males EuPh Europhenome
N normal phenotype
mortality/aging
N
• under normoxic conditions, mice treated with doxycycline from E0 to P25 exhibit no differences in survival at E18.5 or after birth relative to control littermates (J:87622)

homeostasis/metabolism
• after exposure to hyperoxia, doxycycline-treated mice display increased IL-1beta, IL-6, and MIP-2 levels in lung tissue relative to control littermates
• when doxycycline is administered from E0 to P25, adult mice are more susceptible to hyperoxia-induced (95% O2 for 65 hrs) lung injury than oxygen-exposed control littermates, displaying an earlier onset of respiratory symptoms, significantly reduced survival, and severe lung injury as shown by hemorrhage, perivascular and lymphatic edema, loss of bronchiolar and alveolar epithelia, severe epithelial cell necrosis, thickened alveoli, extensive inflammation and frequent airspace enlargement
• intratracheal treatment with exogenous surfactant protein B improves survival and lung histology in doxycycline-treated mice 4 days after hyperoxia exposure

respiratory system
N
• under normoxic conditions, mice treated with doxycycline from E0 to P25 exhibit normal lung size and morphology and normal pulmonary mechanics relative to control littermates (J:87622)
• after exposure to hyperoxia, doxycycline-treated mice display loss of alveolar capillary membrane integrity, perivascular edema, and severe vascular cell necrosis relative to control littermates
• after exposure to hyperoxia, doxycycline-treated mice display increased infiltration by polymorphonuclear cells and alveolar macrophages along with an increased production of IL-1beta, IL-6, and MIP-2 relative to control littermates
• after exposure to hyperoxia, doxycycline-treated mice display widespread alveolar epithelial cell necrosis without apoptosis, hyaline membrane formation, loss of alveolar capillary membrane integrity, and increased inflammation consistent with severe epithelial cell injury
• after exposure to hyperoxia, staining for proSP-C, a selective marker for type II cells, is decreased in doxycycline-treated mice
• after exposure to hyperoxia, doxycycline-treated mice display widespread alveolar epithelial cell necrosis without apoptosis
• after exposure to hyperoxia, doxycycline-treated mice display extensive epithelial cell necrosis in the bronchiolar epithelium
• after exposure to hyperoxia, doxycycline-treated mice display significantly increased lung elastance
• after exposure to hyperoxia, doxycycline-treated mice display significantly increased tissue damping
• doxycycline-treated mice develop acute respiratory distress within 72 hrs of hyperoxia, unlike control littermates which develop severe respiratory symptoms after 5 or more days of continued exposure
• after exposure to hyperoxia, doxycycline-treated mice display altered pulmonary mechanics, indicating a decline in pulmonary function
• however, hysteresivity and newtonian resistance remain unaffected
• after exposure to hyperoxia, doxycycline-treated mice display a significant increase in airway resistance relative to control littermates
• after exposure to hyperoxia, doxycycline-treated mice display reduced lung compliance relative to control littermates
• doxycycline-treated mice exhibit respiratory failure after relatively short periods of hyperoxia
• after exposure to hyperoxia, doxycycline-treated mice show significantly increased BALF protein content and reduced alveolar surfactant phospholipid (saturated phosphatidylcholine) pool sizes relative to control littermates
• after exposure to hyperoxia, SP-B is undetectable while SP-A is significantly decreased in alveolar lavage of doxycycline-treated mice
• after exposure to hyperoxia, doxycycline-treated mice display hyaline membrane formation

immune system
• after exposure to hyperoxia, doxycycline-treated mice display increased IL-1beta, IL-6, and MIP-2 levels in lung tissue relative to control littermates
• after exposure to hyperoxia, doxycycline-treated mice display increased infiltration by polymorphonuclear cells and alveolar macrophages along with an increased production of IL-1beta, IL-6, and MIP-2 relative to control littermates

cardiovascular system
• after exposure to hyperoxia, doxycycline-treated mice display loss of alveolar capillary membrane integrity, perivascular edema, and severe vascular cell necrosis relative to control littermates


Mouse Genome Informatics
cn5
    Sox9tm1Gsr/Sox9tm1Gsr
Tg(SFTPC-rtTA)5Jaw/0
Tg(tetO-cre)1Jaw/0

involves: 129 * 129P2/OlaHsd * C57BL/6
Key:
phenotype observed in females WTSI Wellcome Trust Sanger Institute
phenotype observed in males EuPh Europhenome
N normal phenotype
respiratory system
N
• mice treated with doxycycline from E0.5 display normal postnatal survival and normal lung morphology with no detectable changes in the cellular differentiation or development of peripheral lung epithelium at all stages analyzed (E12.5 to adulthood) (J:95910)

homeostasis/metabolism
N
• mice treated with doxycycline from E0.5 display normal survival and repair after hyperoxia-induced lung injury (95% oxygen for 3 days) relative to control littermates (J:95910)


Mouse Genome Informatics
cn6
    Mettm1Sst/Mettm1Sst
Tg(SFTPC-rtTA)5Jaw/0
Tg(tetO-cre)1Jaw/0

involves: 129 * 129P2/OlaHsd * C57BL/6
Key:
phenotype observed in females WTSI Wellcome Trust Sanger Institute
phenotype observed in males EuPh Europhenome
N normal phenotype
respiratory system
• newborn mice exposed to doxycycline from E14.5 to birth display defective distal lung saccular development due to reduced primary septation
• newborn mice exposed to doxycycline from E14.5 to birth display dilated distal airspaces with only few primary septae, unlike wild-type controls where extensive numbers of saccules are observed


Mouse Genome Informatics
cn7
    Ptentm2Mak/Ptentm2Mak
Tg(SFTPC-rtTA)5Jaw/0
Tg(tetO-cre)1Jaw/0

involves: 129 * 129P2/OlaHsd * C57BL/6 * C57BL/6J
Key:
phenotype observed in females WTSI Wellcome Trust Sanger Institute
phenotype observed in males EuPh Europhenome
N normal phenotype
mortality/aging
• ~10% of mice treated with doxycycline in utero (E10-E16) survive to adulthood but develop spontaneous lung tumors, not observed in wild-type controls during a 90-wk observation period
• the cancer-free survival rates for prenatally doxycycline-treated mice are significantly lower than for controls
• ~90% of mice treated with doxycycline in utero (E10-E16) die within 2 hrs of birth due to respiratory failure
• in contrast, mice treated with doxycycline postnatally (P21-P27 or P84-P90) do not show any neonatal lethality

homeostasis/metabolism
• neonates treated with doxycycline in utero (E10-E16) display a cyanotic skin color
• neonates treated with doxycycline in utero (E10-E16) display significant hypoxia
• neonates treated with doxycycline in utero (E10-E16) display respiratory acidosis
• following urethane treatment, 94% (17 of 18) of mice treated with doxycycline in utero (E10-E16) developed lung tumors (one lung adenocarcinoma, the rest being lung adenomas) relative to only 42% (11 of 26) of wild-type controls (all lung adenomas); also seen in mice treated with doxycycline postnatally (P21-P27)
• both prenatal and postnatal doxycycline treatment resulted in significantly increased numbers and sizes of urethane-induced lung tumors relative to those seen in wild-type controls

respiratory system
• mice treated with doxycycline in utero (E10-E16) display delayed lung development at the terminal sac stage (E17.5 to P0) relative to control mice
• at E19.5, mice treated with doxycycline in utero (E10-E16) show an expanded mesenchymal cell population, due to increased numbers of myofibroblast precursors in the septa
• mesenchymal cell numbers are significantly increased due to enhanced cell proliferation rather than reduced apoptosis
• at the terminal sac stage (E17.5 to P0), mice treated with doxycycline in utero (E10-E16) display fewer saccular structures with a significant delay in the dilatation of the distal tubules relative to control mice
• at birth, mice treated with doxycycline in utero (E10-E16) display septal hyperplasia with increased mesenchymal cells and reduced airspaces relative to controls
• at birth, mice treated with doxycycline in utero (E10-E16) display reduced airspaces relative to controls
• at 8 weeks of age, mice treated with doxycycline postnatally (P21-P27) show a 5.2-fold increase in BASCs and a 4.0-fold increase in side population cells relative to wild-type controls; similar increases are observed in E10-E16 doxycycline treated mice
• neonates treated with doxycycline in utero (E10-E16) display significant bronchiolar epithelial hyperplasia relative to controls
• mice treated with doxycycline postnatally (P21-P27 or P84-P90) display mild bronchiolar epithelial hyperplasia relative to controls; however no significant differences in bronchiolar epithelial differentiation are observed
• at E19.5, mice treated with doxycycline in utero (E10-E16) display increased numbers of undifferentiated cuboidal alveolar epithelial cells of enlarged size relative to controls
• mice treated with doxycycline postnatally (P21-P27 or P84-P90) display mild alveolar epithelial hyperplasia and increased cell size of alveolar epithelial cells relative to controls; however, no significant differences in alveolar epithelial differentiation are observed
• at E19.5, mice treated with doxycycline in utero (E10-E16) display impaired type I cell differentiation, as shown by severely reduced aquaporin-5 (AQP5) immunostaining relative to controls
• at E19.5, mice treated with doxycycline in utero (E10-E16) display immature rounded to cuboidal cells with poorly differentiated cytoplasm, rare apical microvilli, few lamellar bodies, and severely reduced SP-C immunostaining relative to control mice
• at P0, mice treated with doxycycline in utero (E10-E16) also display PAS positivity unlike wild-type control mice
• at E19.5, mice treated with doxycycline in utero (E10-E16) display fewer lamellar bodies than control mice
• at birth, mice treated with doxycycline in utero (E10-E16) show a 1.5-fold increase in total lung cell numbers relative to controls
• at E19.5, the numbers of both alveolar epithelial cells and mesenchymal cells are significantly increased due to enhanced cell proliferation rather than reduced apoptosis
• at E19.5, mice treated with doxycycline in utero (E10-E16) display a much thicker blood-air barrier than control mice
• neonates treated with doxycycline in utero (E10-E16) display irregular breathing and gasping
• ~90% of mice treated with doxycycline in utero (E10-E16) die of respiratory failure
• at E19.5, mice treated with doxycycline in utero (E10-E16) display a significant reduction in the expression levels of surfactant proteins A (SP-A), SP-B, SP-C and SP-D relative to control mice

tumorigenesis
• following urethane treatment, 94% (17 of 18) of mice treated with doxycycline in utero (E10-E16) developed lung tumors (one lung adenocarcinoma, the rest being lung adenomas) relative to only 42% (11 of 26) of wild-type controls (all lung adenomas); also seen in mice treated with doxycycline postnatally (P21-P27)
• both prenatal and postnatal doxycycline treatment resulted in significantly increased numbers and sizes of urethane-induced lung tumors relative to those seen in wild-type controls
• 13 of 14 mice treated with doxycycline in utero (E10-E16) developed lung adenocarcinomas, not observed in any wild-type controls during a 90-wk observation period
• 13 of 15 (87%) of mice treated with doxycycline postnatally (P21-P27) developed spontaneous lung adenocarcinomas, not observed in any wild-type controls during the 40- to 70-wk observation period
• notably, Kras was mutated in 33% of spontaneous lung adenocarcinomas observed in P21-P27 doxycycline treated mice
• 1 of 14 mice treated with doxycycline in utero (E10-E16) developed a lung squamous cell carcinoma

cellular
• at E19.5, mice treated with doxycycline in utero (E10-E16) show an expanded mesenchymal cell population, due to increased numbers of myofibroblast precursors in the septa
• mesenchymal cell numbers are significantly increased due to enhanced cell proliferation rather than reduced apoptosis


Mouse Genome Informatics
cn8
    Hif1atm3Rsjo/Hif1atm3Rsjo
Tg(SFTPC-rtTA)5Jaw/0
Tg(tetO-cre)1Jaw/0

involves: 129 * 129S1/Sv * 129X1/SvJ * C57BL/6
Key:
phenotype observed in females WTSI Wellcome Trust Sanger Institute
phenotype observed in males EuPh Europhenome
N normal phenotype
mortality/aging
• all mice die within an hour of birth when exposed to doxycycline 8 days prior to parturition
• 85% of mice die within an hour of birth when exposed to doxycycline 4 of 6 days prior to parturition

respiratory system
• at birth when mice are exposed to doxycycline prior to parturition
• when mice are exposed to doxycycline prior to parturition, mice exhibit reduced alveolar airspaces unlike wild-type mice
• when mice are exposed to doxycycline prior to parturition, the alveolar surface is lined with immature pneumocytes unlike in wild-type mice
• when mice are exposed to doxycycline prior to parturition, the alveolar septa has only a few scattered type II cells unlike in wild-type mice
• at birth when mice are exposed to doxycycline prior to parturition
• at birth when mice are exposed to doxycycline prior to parturition
• when mice are exposed to doxycycline prior to parturition
• at birth when mice are exposed to doxycycline prior to parturition

homeostasis/metabolism
• at birth when mice are exposed to doxycycline prior to parturition


Mouse Genome Informatics
cn9
    Eya1tm1Rilm/Eya1tm1Rilm
Notch1tm2Rko/Notch1tm2Rko
Tg(SFTPC-rtTA)5Jaw/?
Tg(tetO-cre)1Jaw/?

involves: 129 * 129S1/Sv * 129X1/SvJ * C57BL/6
Key:
phenotype observed in females WTSI Wellcome Trust Sanger Institute
phenotype observed in males EuPh Europhenome
N normal phenotype
respiratory system
• doxycycline treatment leads to restored epithelial branching
• doxycycline treatment partially, but incompletely, restores lung size


Mouse Genome Informatics
cn10
    Ptentm1Hwu/Ptentm1Hwu
Tg(SFTPC-rtTA)5Jaw/0
Tg(tetO-cre)1Jaw/0

involves: 129 * 129S4/SvJae * C57BL/6 * FVB/N
Key:
phenotype observed in females WTSI Wellcome Trust Sanger Institute
phenotype observed in males EuPh Europhenome
N normal phenotype
respiratory system
• doxycyline treated mice exhibit an increase in proliferation of epithelial cells lining conducting airways
• papillary epithelial hyperplasia is seen as early as 4-6 weeks of age in mice treated with doxycycline
• papillary epithelial hyperplasia is characterized by a hypercellular epithelium lining papillae with fibrovascular cores that protrude into the airway lumens
• doxycyline treated mice exhibit an increase in proliferation of nonciliated bronchial and bronchiolar Clara cells
• mice treated with doxycycline exhibit bronchiolar epithelial hyperplasia, producing papillae composed of fibrovascular cores lined by a hypercellular epithelium protruding into the airway lumens consisting of enlarged cells
• mice treated with doxycycline exhibit bronchial epithelial hyperplasia, producing papillae composed of fibrovascular cores lined by a hypercellular epithelium protruding into the airway lumens consisting of enlarged cells

endocrine/exocrine glands
• pulmonary neuroepithelial cell hyperplasia, with a 2-fold increase in the number of pulmonary neuroendocrine cells in mice treated with doxycycline
• however normal respiratory epithelial cell differentiation and respiratory epithelial cell polarity

nervous system
• pulmonary neuroepithelial cell hyperplasia, with a 2-fold increase in the number of pulmonary neuroendocrine cells in mice treated with doxycycline
• however normal respiratory epithelial cell differentiation and respiratory epithelial cell polarity

tumorigenesis
N
• overt pulmonary tumors are not observed in doxycycline treated mice at 6 weeks of age (J:146355)


Mouse Genome Informatics
cn11
    Cebpatm1Dgt/Cebpatm1Dgt
Tg(SFTPC-rtTA)5Jaw/0
Tg(tetO-cre)1Jaw/0

involves: 129 * 129S6/SvEvTac * C57BL/6
Key:
phenotype observed in females WTSI Wellcome Trust Sanger Institute
phenotype observed in males EuPh Europhenome
N normal phenotype
mortality/aging
• although born in Mendelian ratios, most mice exposed to doxycycline from conception die of respiratory failure at birth

respiratory system
• doxycycline-exposed newborn mice show a reduction of airspace, sometimes obliterating the alveolar structure
• doxycycline-exposed newborn mice display increased numbers of Ki-67-positive alveolar cells, indicating increased alveolar cell proliferation
• in addition, neonatal alveolar cells show significantly decreased numbers of TUNEL-positive cells, indicating reduced apoptosis
• doxycycline-exposed newborn mice lack type I alveolar cells
• alveoli of doxycycline-exposed newborn mice are lined by immature cuboidal type II cells with a clear cytosol, round nuclei and high glycogen content, indicating a type II cell differentiation arrest
• immature type II alveolar cells of doxycycline-exposed newborn mice lack lamellar bodies
• doxycycline-exposed newborn mice lack mature type II alveolar cells
• doxycycline-exposed newborn mice display thicker alveolar walls due to marked cellular accumulation
• 86% of mice exposed to doxycycline from conception show signs of respiratory distress within hours after birth
• most mice exposed to doxycycline from conception to birth display respiratory failure
• doxycycline-exposed newborn mice show a marked loss of surfactant protein B (SP-B) by immunostaining
• mRNAs for SP-A and SP-D are significantly down-regulated

liver/biliary system
N
• doxycycline-exposed mice have a normal liver architecture and show normal Cebpa mRNA levels in liver (J:105593)

hematopoietic system
N
• doxycycline-exposed mice exhibit normal granulocytic differentiation in fetal liver and contain granulocytes in peripheral blood (J:105593)


Mouse Genome Informatics
cn12
    Foxm1tm1Rhc/Foxm1tm1Rhc
Tg(SFTPC-rtTA)5Jaw/0
Tg(tetO-cre)1Jaw/0

involves: 129 * 129X1/SvJ * C57BL/6
Key:
phenotype observed in females WTSI Wellcome Trust Sanger Institute
phenotype observed in males EuPh Europhenome
N normal phenotype
mortality/aging
• 82% of mice treated with doxycycline from E7.5 to E14.5 die within the first 24 hrs after birth due to respiratory failure

respiratory system
N
• mice treated with doxycycline during postnatal period P3-P30 show no differences in overall lung morphology or expression of epithelial marker proteins relative to control littermates (J:142246)
• 82% of mice treated with doxycycline from E7.5 to E14.5 display pulmonary congestion
• mice treated with doxycycline from E7.5 to E14.5 display delayed lung maturation, as shown by reduced lung sacculation and mesenchymal thickening prior to birth (E17.5 and E18.5)
• however, branching morphogenesis and proliferation of distal respiratory epithelial cells is normal at E15.5 and E18.5
• no vascular abnormalities are detected at E18.5, as shown by normal Pecam-1 staining
• differentiation of ciliated and Clara cells in conducting airways remains normal
• mice treated with doxycycline from E7.5 to E14.5 display reduced lung sacculation prior to birth
• consistent with delayed lung maturation, peripheral lung tubules remain closed, unlike in control littermates
• mice treated with doxycycline from E7.5 to E14.5 display smaller peripheral saccules at E17.5 and E18.5
• increased mesenchymal thickness prior to birth
• mice treated with doxycycline from E7.5 to E14.5 show delayed differentiation of type I and type II epithelial cells
• mice treated with doxycycline from E7.5 to E14.5 display reduced numbers of squamous type I epithelial cells
• however, type I epithelial cells appear ultrastructurally normal
• mice treated with doxycycline from E7.5 to E14.5 show significantly smaller lamellar bodies in type II cells relative to control littermates
• 82% of mice treated with doxycycline from E7.5 to E14.5 display pulmonary congestion, focal atelectasis, bronchial occlusion, and hyaline membranes lining terminal airways consistent with severe respiratory distress syndrome (RDS)
• ~18% of mice treated with doxycycline from E7.5 to E14.5 survive after birth and exhibit mild RDS with focal atelectasis
• 82% of mice treated with doxycycline from E7.5 to E14.5 display severe respiratory distress
• 82% of mice treated with doxycycline from E7.5 to E14.5 die within the first 24 hrs after birth due to respiratory failure
• mice treated with doxycycline from E7.5 to E14.5 show reduced pulmonary SP-A, SP-B, SP-C, and SP-D mRNA levels at E17.5 relative to control littermates
• SP-B mRNA is reduced to 40% of control values
• mice treated with doxycycline from E7.5 to E14.5 display focal atelectasis
• 82% of mice treated with doxycycline from E7.5 to E14.5 display hyaline membranes lining the terminal airways

cardiovascular system
• 82% of mice treated with doxycycline from E7.5 to E14.5 display pulmonary congestion


Mouse Genome Informatics
cn13
    Cebpatm1Gonz/Cebpatm1Gonz
Tg(SFTPC-rtTA)5Jaw/0
Tg(tetO-cre)1Jaw/0

involves: 129 * 129X1/SvJ * C57BL/6 * FVB/N
Key:
phenotype observed in females WTSI Wellcome Trust Sanger Institute
phenotype observed in males EuPh Europhenome
N normal phenotype
mortality/aging
• mice die within 2 to 3 hours of birth

respiratory system
• capillary beds in lungs are immature
• however, vascular smooth muscle development is normal
• at birth, mice exhibit pulmonary congestion
• between E16.5 and E18.5, mice exhibit reduced dilation of the saccules, thick mesenchyme and a lack of squamous type I cells unlike in wild-type mice
• type I cell maturation is disrupted
• mature type I cells are absent
• type II cell maturation is disrupted and cells lack stored pulmonary surfactant
• mice produce less surfactant protein than wild-type mice
• at birth

cardiovascular system
• capillary beds in lungs are immature
• however, vascular smooth muscle development is normal
• at birth, mice exhibit pulmonary congestion


Mouse Genome Informatics
cn14
    Klf5tm1Jaw/Klf5tm1Jaw
Tg(SFTPC-rtTA)5Jaw/0
Tg(tetO-cre)1Jaw/0

involves: 129 * C57BL/6
Key:
phenotype observed in females WTSI Wellcome Trust Sanger Institute
phenotype observed in males EuPh Europhenome
N normal phenotype
mortality/aging
• doxycycline treated mice die shortly after birth due to respiratory distress

respiratory system
• in doxycycline treated mice, pulmonary mesenchyme is thickened and blood vessels are not found in close proximity to epithelial cells unlike in wild-type mice
• in doxycycline treated mice, lung maturation during saccule development is inhibited
• however, at E15.5 lung development is normal
• at birth, doxycycline treated mice exhibit hypercellular alveolar saccules without the dilated peripheral saccules found in wild-type mice
• saccules in doxycycline treated mice are thickened compared to in wild-type mice
• doxycycline treated mice exhibit thickened lung mesenchyme
• at birth, doxycycline treated mice exhibit a decrease in alveolar luminal area compared to wild-type mice
• at birth, doxycycline treated mice exhibit a decrease in squamous epithelial cells compared to in wild-type mice indicating a lack of alveolar type I cell differentiation
• however, pulmonary epithelial cell proliferation following dooxycycline treatment is normal
• at birth, doxycycline treated mice exhibit a decrease in squamous epithelial cells compared to in wild-type mice
• in doxycycline treated mice, type II cells lack lamellar structures found in wild-type cells
• doxycycline treated mice die shortly after birth due to respiratory distress
• unlike in wild-type mice, no surfactant secretion or Sftpb protein is detected in doxycycline treated mice


Mouse Genome Informatics
cn15
    Itga3tm1Hap/Itga3tm1Hap
Tg(SFTPC-rtTA)5Jaw/?
Tg(tetO-cre)1Jaw/?

involves: 129 * C57BL/6
Key:
phenotype observed in females WTSI Wellcome Trust Sanger Institute
phenotype observed in males EuPh Europhenome
N normal phenotype

Itga3tm1Hap/Itga3tm1Hap Tg(SFTPC-rtTA)5Jaw/? Tg(tetO-cre)1Jaw/? mice exhibit increased bronchoalveolar lavage cellularity at baseline and after bleomycin injury

respiratory system
• bleomycin injury of the lungs leads to less fibrosis three weeks later due to impaired myofibroblast accumulation and reduced type I collagen response
• the number of myofibroblast per field is 4-5 fold less than in controls after bleomycin injury
• there is about a 2-fold increase in the number of type II alveolar cells present in the lungs of mice treated with doxycycline
• cellularity in BAL fluid is almost double that of controls in mice with cre induction
• increase in cellularity is also found after bleomycin injury of the lung
• alveolar septa are thickened with increased deposition of collagen IV in mice with cre induction
• there is a trend towards less compliance in these mice after bleomycin injury than in controls

homeostasis/metabolism
• bleomycin injury of the lungs leads to less fibrosis three weeks later due to impaired myofibroblast accumulation and reduced type I collagen response
• the number of myofibroblast per field is 4-5 fold less than in controls after bleomycin injury


Mouse Genome Informatics
cn16
    Itga3tm1Hap/Itga3tm1Hap
Tg(CAG-Bgeo/GFP)21Lbe/?
Tg(SFTPC-rtTA)5Jaw/?
Tg(tetO-cre)1Jaw/?

involves: 129 * C57BL/6
Key:
phenotype observed in females WTSI Wellcome Trust Sanger Institute
phenotype observed in males EuPh Europhenome
N normal phenotype
respiratory system
• epithelial to mesenchymal transition results from bleomycin-mediated injury of the lung
• only 1.4% of GFP+, epithelium derived cells express mesenchyme markers 17 days after bleomycin injury compared to 7.0% in controls


Mouse Genome Informatics
cn17
    Krastm4Tyj/Kras+
Tg(SFTPC-rtTA)5Jaw/0
Tg(tetO-cre)1Jaw/0

involves: 129/Sv * C57BL/6
Key:
phenotype observed in females WTSI Wellcome Trust Sanger Institute
phenotype observed in males EuPh Europhenome
N normal phenotype
mortality/aging
• death in the early postnatal period

respiratory system
• with doxycycline treatment beginning at E6.5, a dramatic lung branching defect is observed
• at E16.5, lungs show even more severe defects than in Kras:Meox2-cre embryos, with large epithelial-lined pouches in place of finely branched network of airways seen in wild-type
• branching defect persists through late gestation leading to early postnatal lethality
• branching defect originates in epithelium rather than mesenchyme
• markers of ciliated and Clara cells in the bronchi are significantly reduced at E18.5 compared to controls, indicating block in differentiation of lung epithelium


Mouse Genome Informatics
cn18
    Nedd4ltm1.1Dro/Nedd4ltm1.1Dro
Tg(SFTPC-rtTA)5Jaw/0
Tg(tetO-cre)1Jaw/0

involves: 129P2/OlaHsd * C57BL/6 * FVB/N * SJL
Key:
phenotype observed in females WTSI Wellcome Trust Sanger Institute
phenotype observed in males EuPh Europhenome
N normal phenotype
mortality/aging
• mice die between 2 and 3 weeks of age likely from airway obstruction and asphyxiation

respiratory system
• mice exhibit large dense patches consisting of infiltrating neutrophils that is not secondary to bacterial infection unlike control mice
• however, treatment with amiloride reduces inflammation
• mice exhibit decreased lung wet/dry ratio compared with control mice
• however, treatment with amiloride improves lung defects
• mice exhibit cystic fibrosis-like defects unlike control mice
• mice exhibit increased nonciliated mucus secreting (mostly goblet) cells in the trachea unlike control mice
• mice exhibit increased nonciliated mucus secreting (mostly goblet) cells in the trachea unlike control mice
• airway periciliary liquid layer in the trachea is decreased in height compared to in control mice

immune system
• mice exhibit large dense patches consisting of infiltrating neutrophils that is not secondary to bacterial infection unlike control mice
• however, treatment with amiloride reduces inflammation

homeostasis/metabolism
• mice exhibit cystic fibrosis-like defects unlike control mice


Mouse Genome Informatics
cn19
    Lama5tm1Jhm/Lama5tm2Jhm
Tg(SFTPC-rtTA)5Jaw/?
Tg(tetO-cre)1Jaw/?

involves: 129S1/Sv * 129X1/SvJ
Key:
phenotype observed in females WTSI Wellcome Trust Sanger Institute
phenotype observed in males EuPh Europhenome
N normal phenotype
mortality/aging
• animals exposed to doxycycline from E6.5 die within a few hours of birth from respiratory failure

respiratory system
• severely reduced density of lung capillary network in newborn animals exposed to doxycycline from E6.5, associated with reduced VEGF expression in mutant lungs
• areas of thin lung mesenchyme and upregulation of integrin alpha 3 (Lama5 receptor) in newborn animals exposed to doxycycline from E6.5
• areas of thin lung mesenchyme in newborn animals exposed to doxycycline from E6.5
• total lung parenchyma is reduced
• airspaces of newborn animals exposed to doxycycline from E6.5 are filled with amorphous proteinaceous material and cellular debris not seen in controls
• delayed or impaired differentiation of distal alveolar epithelium in newborn animals exposed to doxycycline from E6.5
• mutant peripheral airspaces are often lined with cuboidal epithelium
• virtual absence of alveolar type I cells in newborn animals exposed to doxycycline from E6.5
• significant reduction of alveolar type II cells in newborn animals exposed to doxycycline from E6.5
• enlarged distal airspaces in newborn animals exposed to doxycycline from E6.5
• newborn animals exposed to doxycycline from E6.5 display labored breathing

homeostasis/metabolism
• newborn animals exposed to doxycycline from E6.5 display cyanosis

cardiovascular system
• severely reduced density of lung capillary network in newborn animals exposed to doxycycline from E6.5, associated with reduced VEGF expression in mutant lungs

cellular
• in lungs of newborn animals exposed to doxycycline starting at E6.5
• in lungs of newborn animals exposed to doxycycline from E6.5


Mouse Genome Informatics
cn20
    Gpr116tm1.1Bstc/Gpr116tm1.2Bstc
Tg(SFTPC-rtTA)5Jaw/0
Tg(tetO-cre)1Jaw/0

involves: 129S4/SvJae * C57BL/6 * C57BL/6J
Key:
phenotype observed in females WTSI Wellcome Trust Sanger Institute
phenotype observed in males EuPh Europhenome
N normal phenotype
homeostasis/metabolism
• increased phosphatidylcholine in the bronchoalveolar lavage fluid of doxycycline-treated mice
• in the bronchoalveolar lavage fluid of doxycycline-treated mice

respiratory system
• increased surfactant protein A, B, C and D in the whole lung lysate of doxycycline-treated mice


Mouse Genome Informatics
cn21
    Pcyt1atm1Irt/Pcyt1atm1Irt
Tg(SFTPC-rtTA)5Jaw/0
Tg(tetO-cre)1Jaw/Tg(tetO-cre)1Jaw

involves: C57BL/6J * FVB/N
Key:
phenotype observed in females WTSI Wellcome Trust Sanger Institute
phenotype observed in males EuPh Europhenome
N normal phenotype
mortality/aging
• all newborn mice exposed to doxycycline from E6.5 to E7.5 die within 10 min of delivery
• all mice exposed to doxycycline at either E10.5 or E12.5 and continuing until birth (E18.5 to E19.5) exhibit neonatal lethality
• only 10% of mice exposed to doxycycline from E16.5 to term exhibit neonatal death
• neonatal viability is also significantly reduced when doxycycline is administered between E8.5 and E12.5

respiratory system
• capillary leakage and macrophage accumulation within the alveolar space of doxycycline-exposed newborn mice
• pulmonary congestions in perinatal lung sections from doxycycline-exposed mice
• at E19.5 (birth), dilation of peripheral lung saccules is reduced and the septa remain thickened in doxycycline-exposed mice
• in doxycycline-exposed mice, type II alveolar cells display Golgi complex abnormalities, aberrant lamellar body formation, fewer and shorter apical microvilli, and freqeunt accumulation of lipid droplets consistent with increased pulmonary triglyceride levels
• in contrast, the ultrastructure of type I alveolar cells remains normal
• fewer secretary vesicles or mature lamellar bodies in doxycycline-exposed mice
• at E19.5 (birth), the number of type II alveolar cells is markedly reduced in the terminal lung saccules of all doxycycline-exposed mice
• nondilated alveolar saccules in doxycycline-exposed newborn mice
• in doxycycline-exposed mice, alveolar walls are thickened but still lined with organized type I and type II cells
• all mice exposed to doxycycline from E6.5 to E7.5 develop severe respiratory distress immediately after birth
• also seen in all mice exposed to doxycycline at either E10.5 or E12.5 and continuing until birth (E18.5 to E19.5)
• the phosphatidylcholine (PtdCho) content is significantly reduced when doxycycline is administered between E8.5 and E12.5 or between E12.5 and E16.5, but not prior to E9.5
• at E17.5, the PtdCho content is significantly reduced in mice exposed to doxycycline from E0 to E17, with a severe decrease in the proportion of dipalmitoyl-PtdCho, suggesting a selective depletion of the C16:0 fatty acid; however, neither phosphatidylethanolamine nor cholesterol is significantly reduced
• total BAL fluid contains significantly less phospholipid per lung; both the large (LA) and small (SA) aggregate fractions are severely depleted in total phospholipid
• the reduction in surfactant protein is less than that in total phospholipid resulting in a 4.7-, 2.8-, and 7.4-fold increase in the protein:phospholipid ratio in BAL, LA, and SA, respectively
• in mice exposed to doxycycline from E0 to E17, phosphatidylcholine (PtdCho) formation is blocked and surfactant fatty acid synthesis is shunted into the triglyceride pool
• surfactant protein SP-A, SP-C, and SP-D levels are significantly reduced, whereas SP-B protein content is elevated
• focal or extensive atelectasis seen in perinatal lung sections from mice exposed to doxycycline from E6.5 to E7.5
• all neonatal lungs from mice exposed to doxycycline from E6.5 to E7.5 fail to inflate and sink in saline, unlike wild-type neonatal lungs
• however, lungs of viable mice exposed to doxycycline from E16.5 to term appear inflated and show normal lung morphology
• hyaline membrane formation seen in perinatal lung sections from mice exposed to doxycycline from E6.5 to E7.5

homeostasis/metabolism
• all newborn mice exposed to doxycycline from E6.5 to E7.5 become cyanotic
• significantly increased triglyceride levels in neonatal lungs from mice exposed to doxycyclin from E0 to E17, with a similar increase in the proportion of species containing palmitic acid (C16:0), esp. in the species containing 48 and 60 carbons

cardiovascular system
• capillary leakage and macrophage accumulation within the alveolar space of doxycycline-exposed newborn mice
• pulmonary congestions in perinatal lung sections from doxycycline-exposed mice


Mouse Genome Informatics
cn22
    Shhtm2Amc/Shhtm2Amc
Tg(SFTPC-rtTA)5Jaw/0
Tg(tetO-cre)1Jaw/0

involves: FVB/N
Key:
phenotype observed in females WTSI Wellcome Trust Sanger Institute
phenotype observed in males EuPh Europhenome
N normal phenotype
mortality/aging
• mutants die shortly after birth when doxycycline is administered throughout gestation
• in the absence of doxycycline mutants are viable

respiratory system
• lung and airway malformations are seen when doxycycline exposure occurs between E0.5 and E13.5
• doxycycline exposure after E13.5 does not result in any pulmonary or extrapulmonary abnormalities
• branching morphogenesis is abnormal
• lungs are hypoplastic when doxycycline is administered throughout gestation
• peripheral tubule dilation is seen after doxycycline exposure
• cysts that contain neuroepithelial cells are seen in the peripheral lung tissue
• tracheal abnormalities are seen
• doxycycline exposure before E8.5 or after E13.5 does not result in tracheal abnormalities
• the cartilaginous rings that normal surround the trachea are malformed with incomplete rings found along the ventral midline after doxycycline exposure
• fewer cartilaginous rings are seen after doxycycline exposure

skeleton
• the cartilaginous rings that normal surround the trachea are malformed with incomplete rings found along the ventral midline after doxycycline exposure
• fewer cartilaginous rings are seen after doxycycline exposure


Mouse Genome Informatics
cn23
    Shhtm1Amc/Shhtm2Amc
Tg(SFTPC-rtTA)5Jaw/0
Tg(tetO-cre)1Jaw/0

involves: FVB/N
Key:
phenotype observed in females WTSI Wellcome Trust Sanger Institute
phenotype observed in males EuPh Europhenome
N normal phenotype
mortality/aging
• mutants die shortly after birth when doxycycline is administered throughout gestation
• in the absence of doxycycline treatment mutants are viable

respiratory system
• lung and airway malformations are seen when doxycycline exposure occurs between E0.5 and E13.5
• doxycycline exposure after E13.5 does not result in any pulmonary or extrapulmonary abnormalities
• branching morphogenesis is abnormal with doxycycline treatment
• lungs are hypoplastic after doxycycline exposure
• peripheral tubule dilation is seen with doxycycline exposure
• cysts are seen in the peripheral lung tissue
• tracheal abnormalities are seen
• doxycycline exposure before E8.5 or after E13.5 does not result in tracheal abnormalities
• the cartilaginous rings that normal surround the trachea are malformed with incomplete rings found along the ventral midline after doxycycline exposure
• fewer cartilaginous rings are seen with doxycycline treatment

skeleton
• the cartilaginous rings that normal surround the trachea are malformed with incomplete rings found along the ventral midline after doxycycline exposure
• fewer cartilaginous rings are seen with doxycycline treatment


Mouse Genome Informatics
cx24
    Fgfr3tm1Dor/Fgfr3tm1Dor
Tg(SFTPC-rtTA)5Jaw/0
Tg(tetO-Fgf9,-EGFP)#Dor/0

involves: 129S6/SvEvTac * C57BL/6J * FVB
Key:
phenotype observed in females WTSI Wellcome Trust Sanger Institute
phenotype observed in males EuPh Europhenome
N normal phenotype
tumorigenesis
• at 1 week or 1 month of induction with doxycycline, mutants do not exhibit formation of lung tumors and lung histology remains normal


Mouse Genome Informatics
cx25
    Tg(SFTPC-rtTA)5Jaw/0
Tg(tetO-Fgf9,-EGFP)#Dor/0

involves: FVB
Key:
phenotype observed in females WTSI Wellcome Trust Sanger Institute
phenotype observed in males EuPh Europhenome
N normal phenotype
tumorigenesis
• 2 of 5 mutants that develop ascites after 4 months of doxycycline induction contain cells with malignant cytology
• one day following doxycycline administration, adult mutants exhibit formation of small nodules (epithelial clusters) on the lung surface
• one day following doxycycline administration, adult mutants exhibit formation of small nodules (epithelial clusters) on the lung surface
• papillary adenoma and papillary adenocarcinoma develop in mice treated with doxycycline for 4 and 8 days, respectively
• small tumor nodules and large tumor nodules persist in the lungs of mutants treated with doxycycline for 2-4 days followed by 1 month of doxycycline and in mutants treated with doxycycline for 2 weeks followed by 9 and 18 weeks of withdrawal, respectively
• after 4 days of doxycycline induction, nodules are histologically consistent with papillary adenoma
• after 8 days of doxycycline induction, the cells forming papillary structures become atypical with larger and hyperchromatic nuclei, consistent with papillary adenocarcinoma

mortality/aging
• doxycycline treated adults show a median survival of 89 days and die due to respiratory failure

respiratory system
• doxycycline treated adults die due to respiratory failure

homeostasis/metabolism
• mutants surviving 4 months of doxycycline induction develop ascites

Mouse Models of Human Disease
OMIM IDRef(s)
Lung Cancer 211980 J:204282


Mouse Genome Informatics
cx26
    Shhtm1Amc/Shhtm1Amc
Tg(SFTPC-rtTA)5Jaw/0
Tg(tetO-Shh)1Jaw/0

involves: FVB/N
Key:
phenotype observed in females WTSI Wellcome Trust Sanger Institute
phenotype observed in males EuPh Europhenome
N normal phenotype
mortality/aging
• mutants die shortly after birth even when doxycycline is administered throughout gestation

respiratory system
• a significant increase in peripheral lung tissue and relatively normal branching morphogenesis are seen with doxycycline treatment; however, lobulation of the lungs is not restored
• doxycycline treatment does not restore tracheal-bronchial cartilaginous ring formation

skeleton
• doxycycline treatment does not restore tracheal-bronchial cartilaginous ring formation


Mouse Genome Informatics
cx27
    Tg(tetO-Vegfa)90Ala/?
Tg(SFTPC-rtTA)5Jaw/?

involves: FVB/N
Key:
phenotype observed in females WTSI Wellcome Trust Sanger Institute
phenotype observed in males EuPh Europhenome
N normal phenotype
respiratory system
• administration of doxycycline to pregnant mother and consequent VEGF-A164 expression in peripheral respiratory epithelial cells of E10.5 to E16.5 embryo caused altered peripheral lung morphogenesis with disrupted vascular pattern formation


Mouse Genome Informatics
cx28
    Tg(SFTPC-rtTA)5Jaw/0
Tg(tetO/CMV-KRAS*G12C)9.1Msmi/0

involves: FVB/N
Key:
phenotype observed in females WTSI Wellcome Trust Sanger Institute
phenotype observed in males EuPh Europhenome
N normal phenotype
respiratory system
• after 12 days of doxycycline (DOX) treatement, small, hyperplastic lung foci are detected; untreated mice have normal lungs
• after 5 weeks of DOX treatment, extensive epithelial hyperplasia of alveolar region of lung is observed; untreated mice have normal lungs
• alveolar lipoproteinosis is regularly found, indicating abnormal surfactant metabolism

tumorigenesis
• after 3 months treatment, visible macroscopic lesions are found; tumor incidence at 3 months is 55%, with multiplicity of 1.7 tumors/mouse
• lesions are <1mm in size
• early hyperplastic lesions are of alveologenic origin
• at 6 and 9 months DOX treatment, visible lesions increase in number; multiplicity is 10.2 and 12.5 tumors/mouse after 9 and 12 months, lower than Scgb1a1/KRAS bitransgenic mice; treated monotransgenic mice show no incidence
• when DOX treatment was stopped after 9 months, within 2 weeks only 4 tumors are visible on lung surface and by 1 month, no tumors are visible, and with minimal hyperplastic foci microscopically detectable, showing no proliferation (or apoptosis)


Mouse Genome Informatics
cx29
    Tg(SFTPC-rtTA)5Jaw/0
Tg(tetO-PLAGL2)P3Ysy/0

involves: FVB/N
Key:
phenotype observed in females WTSI Wellcome Trust Sanger Institute
phenotype observed in males EuPh Europhenome
N normal phenotype
respiratory system
• doxycycline-treated mice develop centrilobular emphysema and in severe cases such mice exhibit total destruction of an entire lobe
• 90% of doxycycline-treated female mice develop emphysema
• doxycycline-treated female mice exhibit a shift in the inspiratory pressure volume curve to the left indicating an increase in respiratory system compliance compared with wild-type mice

cellular
• doxycycline-treated mice exhibit an increase in apoptosis in the peripheral airway epithelial cells adjacent to the emphysematous lesions

Mouse Models of Human Disease
OMIM IDRef(s)
Emphysema, Hereditary Pulmonary 130700 J:152422


Mouse Genome Informatics
cx30
    Tg(SFTPC-rtTA)5Jaw/0
Tg(tetO-MYC)36Bop/0

Not Specified
Key:
phenotype observed in females WTSI Wellcome Trust Sanger Institute
phenotype observed in males EuPh Europhenome
N normal phenotype
mortality/aging
• mice fed a diet supplemented with DOX to stimulate transactivating function of the rtTA protein and induce MYC expression exhibit reduced lifespan
• treatment of non-DOX treated mutants with the mutagen N-methyl-N-nitrosourea (MNU) accelerates the rate of demise

respiratory system
• mice treated with DOX develop alveolar hyperplasia
• alveolar hyperplasia forms as clusters of cells that expand the alveolar septa, reaches a maximum after 4 days of DOX treatment and then resolves due to apoptosis of the hyperplastic cells

tumorigenesis
• 5.9% of DOX treated mice exhibit metastases
• 100% of tumors show activating Kras mutations
• mice treated with DOX develop papillary adenomas
• 31.6% penetrance of adenocarcionomas in untreated mice and 57.9% penetrance in DOX treated mice
• mutants treated with DOX and then MNU have significantly lower number of tumors compared to mutagenized mice not treated with DOX


Mouse Genome Informatics
cx31
    Tg(SFTPC-rtTA)5Jaw/0
Tg(tetO-Fgf9,-EGFP)#Dor/0

Not Specified
Key:
phenotype observed in females WTSI Wellcome Trust Sanger Institute
phenotype observed in males EuPh Europhenome
N normal phenotype
respiratory system
• doxycycline treated embryos exhibit an extended domain of blood vessels into the expanded lung mesenchyme at E13.5
• doxycycline treated embryos exhibit increased luminal space, fewer epithelial airways and a wide band of mesenchyme separating epithelial ducts at E14.5
• doxycycline treated embryos exhibit a reduction in epithelial branching at E11.5 and E12.5
• beginning at E12.5, doxycycline treated embryos exhibit an arrest in branching and luminal dilation
• doxycycline treated embryos exhibit a large mesenchymal expansion in the lungs at E11.5 and E12.5
• doxycycline treated embryos show an absence of smooth muscle in the sub-epithelial compartment of lungs at E14.5, although it is present surrounding large blood vessels
• beginning at E12.5, doxycycline treated embryos exhibit enlarged lung size

cardiovascular system
• doxycycline treated embryos exhibit an extended domain of blood vessels into the expanded lung mesenchyme at E13.5


Mouse Genome Informatics
cx32
    Gt(ROSA)26Sortm1(tetO-Sox9)Msan/Gt(ROSA)26Sor+
Tg(SFTPC-rtTA)5Jaw/0

Not Specified
Key:
phenotype observed in females WTSI Wellcome Trust Sanger Institute
phenotype observed in males EuPh Europhenome
N normal phenotype
mortality/aging
• when dox treatment was started at E15.5, all 3 double mutants died at birth

respiratory system
• in dox treated mice, distal epithelium remains columnar failing to undergo the columnar to squamous transition

cellular
• when dox treatment is started at E9.5 or E15.5, terminal differentiation of airway cells is inhibited and all differentiated cells are Sox9-negative