Phenotypes for Pten Tg(SFTPC-rtTA)5Jaw Tg(tetO-cre)1Jaw MGI:4950587 MGI Mouse

decreased survivor rate ( J:127405 )

• ~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

neonatal lethality, incomplete penetrance ( J:127405 )

• ~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

cyanosis ( J:127405 )

• neonates treated with doxycycline in utero (E10-E16) display a cyanotic skin color

hypoxia ( J:127405 )

• neonates treated with doxycycline in utero (E10-E16) display significant hypoxia

respiratory acidosis ( J:127405 )

• neonates treated with doxycycline in utero (E10-E16) display respiratory acidosis

increased incidence of tumors by chemical induction ( J:127405 )

• 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

pulmonary hyperplasia ( J:127405 )

• 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

respiratory acidosis ( J:127405 )

• neonates treated with doxycycline in utero (E10-E16) display respiratory acidosis

increased lung adenocarcinoma incidence ( J:127405 )

• 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

increased lung squamous cell carcinoma incidence ( J:127405 )

• 1 of 14 mice treated with doxycycline in utero (E10-E16) developed a lung squamous cell carcinoma

abnormal lung development ( J:127405 )

• 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

increased mesenchymal cell proliferation involved in lung development ( J:127405 )

• 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

abnormal lung saccule morphology ( J:127405 )

• 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

small lung saccule ( J:127405 )

• at birth, mice treated with doxycycline in utero (E10-E16) display reduced airspaces relative to controls

increased bronchioalveolar stem cell number ( J:127405 )

• 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

bronchiolar epithelial hyperplasia ( J:127405 )

• 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

abnormal pulmonary alveolus epithelial cell morphology ( J:127405 )

• 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

abnormal type I pneumocyte morphology ( J:127405 )

• 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

abnormal type II pneumocyte morphology ( J:127405 )

• 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

decreased alveolar lamellar body number ( J:127405 )

• at E19.5, mice treated with doxycycline in utero (E10-E16) display fewer lamellar bodies than control mice

abnormal alveolocapillary membrane morphology ( J:127405 )

• at E19.5, mice treated with doxycycline in utero (E10-E16) display a much thicker blood-air barrier than control mice

respiratory distress ( J:127405 )

• neonates treated with doxycycline in utero (E10-E16) display irregular breathing and gasping

respiratory failure ( J:127405 )

• ~90% of mice treated with doxycycline in utero (E10-E16) die of respiratory failure

decreased surfactant secretion ( J:127405 )

• 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