Mouse Genome Informatics
hm1
    Ihhtm1Amc/Ihhtm1Amc
involves: 129S1/Sv * 129X1/SvJ
Key:
phenotype observed in females WTSI Wellcome Trust Sanger Institute
phenotype observed in males EuPh Europhenome
N normal phenotype
growth/size
• at birth, homozygotes show a foreshortened snout
• at birth, homozygotes are consistently shorter than wild-type mice
• at birth mutants display severe short-limb dwarfism

skeleton
• in homozygotes, most skeletal elements are present in the right position and in the right number; however, all elements of the axial and appendicular skeletons exhibit dwarfism
• at 18.5 dpc, some of the wrist bones of homozygotes appear partly fused
• mutant long bones fail to show any signs of calcification at 14.5 dpc, as expected; instead, calcification is first noted at 16.5 dpc in mutant scapula and humerus, and slightly later in radius and ulna (J:57297)
• depletion of non-mineralized cartilage at articular ends of long bones (J:73071)
• at 18.5 dpc, the mutant humerus and ulna remain partly fused
• at 18.5 dpc, mutant humeri display no identifiable cortical bone, even in vascularized areas of the perichondrium
• at birth, mutant long bones are one-third the length of wild-type long bones
• growth retardation of tibia
• length of scapula is shorter
• at birth, homozygotes display a foreshortened mandible
• at birth, homozygotes show a rounded skull
• mutant ribs do not display excessive calcification
• homozygotes have significantly shortened ribs
• at 18.5 dpc, homozygotes show no osteocalcin expression in endochondral bones of the appendicular or axial skeleton, indicating absence of mature osteoblasts in mutant long bones
• in contrast, mature osteoblasts are present in mutant bones formed by intramembranous ossification (e.g. flat bones of the skull, mandible, and clavicle)
• 18.5 dpc, mutant humeri display no identifiable trabecular bone in the primary spongiosa
• homozygotes display ectopic maturation of chondrocytes: chondrocyte differentiation is initially delayed, but when it occurs, hypertrophic cells fail to exhibit a stacked columnar organization and occupy inappropriate positions close to articular surfaces (J:57297)
• premature chondrocyte hypertrophy, resulting in depletion of non-mineralized cartilage at articular ends of long bones (J:73071)
• decrease in chondrocyte proliferation at E14.5 (J:73071)
• at 18.5 dpc, homozygotes show abnormal joint formation
• skeletal growth retardation
• although initial cartilage elements develop normally, 13.5-dpc mutant forelimbs show a slight reduction in each cartilage element relative to wild-type; this size difference is clearly visible at 14.5 dpc
• as early as 12.5 dpc, mutant humeri show a ~50% reduction in chondrocyte proliferation; in addition, the length of proliferative zone is severely reduced
• at 13.5 dpc, mutant humeri show absence of typical hypertrophic chondrocytes
• at 14.5 dpc, some hypertrophic cells are found in the center of mutant humeri but are neither as large nor as well-organized as those of wild-type bones
• such hypertrophic cells are surrounded by less mature chondrocytes and show no signs of vascularization or cortical bone formation
• reduced chondrocyte proliferation and severe short-limb dwarfism are seen
• in homozygotes, appendicular skeletal elements fail to ossify
• at 16.5 dpc, mutant humeri show ectopic initial calcification in the center of cartilage only, suggesting that mineralization occurs in cartilage and not in association with a bone collar
• by 18.5 dpc, ectopic calcification extends closer to the articular surfaces in mutant bones, including the humerus, sternum, vertebrae, and cartilaginous synchondroses of the base of the skull
• homozygotes exhibit absence of endochondral bone formation prior to birth
• in homozygous newborns, most endochondral bones are shorter and relatively malformed

limbs/digits/tail
• homozygotes display failure of digit segmentation: at 18.5 dpc, mutant digits remain unsegmented and uncalcified (J:57297)
• failure of digit segmentation and ossification (J:73071)
• at 13.5 dpc, homozygotes display visibly shortened forelimbs
• at 18.5 dpc, the mutant humerus and ulna remain partly fused
• at 18.5 dpc, mutant humeri display no identifiable cortical bone, even in vascularized areas of the perichondrium
• growth retardation of tibia
• at 18.5 dpc, some of the wrist bones of homozygotes appear partly fused
• at 13.5 dpc, homozygotes display visibly shortened forelimbs (J:57297)
• at birth, homozygotes display significant dwarfism of the limbs (J:57297)
• 60-80% reduction in the length of the stylopod and the zeugopod at birth (J:73071)

vision/eye
N
• no rosettes are observed in the retina (J:78708)
• astrocyte precursor cells at the optic disc and in the optic nerve develop normally (J:83530)

mortality/aging
• homozygotes that develop to term die at birth due to respiratory failure
• about 50% of homozygotes die at midgestation between 10.5 and 12.5 dpc, probably as a result of circulatory defects
• some lethality also occurs at later stages of gestation

craniofacial
• at birth, homozygotes display a foreshortened mandible
• at birth, homozygotes show a rounded skull
• at birth, homozygotes show a foreshortened snout

respiratory system


Mouse Genome Informatics
hm2
    Ihhtm1Amc/Ihhtm1Amc
involves: 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
embryogenesis
• yolk sacs have fewer and thinner blood vessels compared to wild-type at E9.5

cardiovascular system
• yolk sacs have fewer and thinner blood vessels compared to wild-type at E9.5


Mouse Genome Informatics
hm3
    Ihhtm1Amc/Ihhtm1Amc
involves: 129S1/Sv * 129X1/SvJ * C57BL/6J * CBA/J
Key:
phenotype observed in females WTSI Wellcome Trust Sanger Institute
phenotype observed in males EuPh Europhenome
N normal phenotype
digestive/alimentary system
N
• at 18.5 dpc, homozygotes exhibit no intestinal transformation of the stomach epithelium (J:62158)
• at 18.5 dpc, homozygotes display a smaller gastrointestinal tract relative to wild-type
• at 18.5 dpc, all homozygotes display an obvious malrotation of the gut, in the absence of reversions in gut situs
• at 18.5 dpc, homozygotes display a significant dilation of parts of the colon as well as a thin wall
• at 18.5 dpc, 50% of homozygotes display an aganglionic megacolon
• at 18.5 dpc, homozygotes show a significant dilation of the small intestine
• at 18.5 dpc, homozygotes show a 34% reduction in thickness of the circular smooth muscle layer along the small intestine
• at this stage, the size of mutant villi is markedly reduced concomitant with a 54% decrease in epithelial stem cell proliferation between and at the base of villi
• at 18.5 dpc, homozygotes show a 45% reduction in the number of cholecystokinin-producing cells of the duodenum
• at 18.5 dpc, no duodenal stenosis is observed

growth/size
• at 18.5 dpc, mutant embryos have an overall reduced size relative to wild-type embryos

nervous system
• at 18.5 dpc, enteric neurons are completely absent along parts of the small intestine and in dilated portions of the colon

endocrine/exocrine glands
• at 18.5 dpc, 43% of homozygotes exhibit an annular pancreas

muscle
• at 18.5 dpc, homozygotes show a 34% reduction in thickness of the circular smooth muscle layer along the small intestine

Mouse Models of Human Disease
OMIM IDRef(s)
Pancreas, Annular 167750 J:62158


Mouse Genome Informatics
ht4
    Ihhtm1Amc/Ihh+
involves: 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
skeleton
• modest shortening of the growth plate


Mouse Genome Informatics
cn5
    Ihhtm1Amc/Ihh+
Pth1rtm1Hmk/Pth1rtm2Hmk
Tg(Bglap2-cre)1Kry/0

involves: 129S1/Sv * 129S4/SvJae * 129X1/SvJ * C57BL/6 * FVB
Key:
phenotype observed in females WTSI Wellcome Trust Sanger Institute
phenotype observed in males EuPh Europhenome
N normal phenotype
skeleton
• growth plate is expanded, however less than in compound heterozygous mice that contain Ihh


Mouse Genome Informatics
cn6
    Ihhtm1Amc/Ihhtm2Amc
Pth1rtm1Hmk/Pth1rtm2Hmk
Tg(Bglap2-cre)1Kry/0

involves: 129S1/Sv * 129S4/SvJae * 129X1/SvJ * C57BL/6 * FVB
Key:
phenotype observed in females WTSI Wellcome Trust Sanger Institute
phenotype observed in males EuPh Europhenome
N normal phenotype
skeleton
• ectopic hypertrophic differentiation in growth plates, however do not observe elongation of the columnar region


Mouse Genome Informatics
cn7
    Gt(ROSA)26Sortm2(Gli2*)Flng/Gt(ROSA)26Sor+
Ihhtm1Amc/Ihhtm1Amc
Tg(Col2a1-cre)3Amc/0

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
• mice die at birth

skeleton
N
• vascularization and bone formation in the diaphysis are normal (J:154905)
• similar to in Ihhtm1Amc homozygotes, orthotopic osteoblast differentiation is impaired as determined by marker expression
• at E15.5 and E18.5, the proliferative zone is slightly larger than in Ihhtm1Amc homozygotes but smaller than in wild-type mice
• vascularization of the hypertrophic zone is improved compared to in Ihhtm1Amc homozygotes
• columnar organization of chondrocytes is partially restored compared to in Ihhtm1Amc homozygotes but is still disorganized compared to in wild-type mice
• at E18.5, mice fail to exhibit bone deposition in the perichondrium flanking the hypertrophic regions where the bone collar normally forms in the long bones of wild-type mice

cellular
• similar to in Ihhtm1Amc homozygotes, orthotopic osteoblast differentiation is impaired as determined by marker expression


Mouse Genome Informatics
cn8
    Gt(ROSA)26Sortm3(Runx2)Flng/Gt(ROSA)26Sortm3(Runx2)Flng
Ihhtm1Amc/Ihhtm1Amc
Tg(Col2a1-cre)3Amc/0

involves: 129S1/Sv * 129X1/SvJ
Key:
phenotype observed in females WTSI Wellcome Trust Sanger Institute
phenotype observed in males EuPh Europhenome
N normal phenotype
skeleton
• the nonhypertrophic chondrocyte zone in the tibia is reduced to a greater extent than in Ihhtm1Amc homozygotes
• hypertrophic chondrocytes exhibit accelerated progression from early stage to late stage hypertrophy compared with control mice
• thin bone collar

cellular


Mouse Genome Informatics
cn9
    Gli3Xt-J/Gli3Xt-J
Gt(ROSA)26Sortm2(Gli2*)Flng/Gt(ROSA)26Sor+
Ihhtm1Amc/Ihhtm1Amc
Tg(Col2a1-cre)3Amc/0

involves: 129S1/Sv * 129X1/SvJ * C3H/HeJ
Key:
phenotype observed in females WTSI Wellcome Trust Sanger Institute
phenotype observed in males EuPh Europhenome
N normal phenotype
mortality/aging
• mice die at birth

skeleton
N
• unlike in Ihhtm1Amc Gli3Xt-J homozygotes the marrow cavity and hypertrophic chondrocyte are normal (J:154905)
• the growth region cartilage is longer than in wild-type mice
• the columnar zone contains areas of disorganization unlike in wild-type mice
• however, orthotopic bone collar formation is normal unlike in Ihhtm1Amc homozygotes

growth/size
• while larger than Ihhtm1Amc homozygotes at E18.5, mice are smaller than wild-type mice

limbs/digits/tail
• while larger than in Ihhtm1Amc homozygotes at E18.5, limbs are shorter than in wild-type mice


Mouse Genome Informatics
cx10
    Ihhtm1Amc/Ihhtm1Amc
Shhtm1Amc/Shhtm1Amc

involves: 129/Sv * C57BL/6J * CBA/J
Key:
phenotype observed in females WTSI Wellcome Trust Sanger Institute
phenotype observed in males EuPh Europhenome
N normal phenotype
embryogenesis
• double homozygotes arrest at early somite stages


Mouse Genome Informatics
cx11
    Gt(ROSA)26Sortm2(Gli2*)Flng/Gt(ROSA)26Sor+
Ihhtm1Amc/Ihhtm1Amc

involves: 129S1/Sv * 129X1/SvJ
Key:
phenotype observed in females WTSI Wellcome Trust Sanger Institute
phenotype observed in males EuPh Europhenome
N normal phenotype
skeleton
• orthotopic osteoblast differentiation is impaired as determined by marker expression
• the hypertrophic zone lacks vascularization unlike in wild-type mice
• columnar organization prior to hypertrophy is absent unlike in wild-type mice

cellular
• orthotopic osteoblast differentiation is impaired as determined by marker expression


Mouse Genome Informatics
cx12
    Gli3Xt-J/Gli3Xt-J
Ihhtm1Amc/Ihhtm1Amc

involves: 129S1/Sv * 129X1/SvJ * C3H/HeJ
Key:
phenotype observed in females WTSI Wellcome Trust Sanger Institute
phenotype observed in males EuPh Europhenome
N normal phenotype
skeleton
• the marrow cavity does not develop unlike in wild-type mice
• however, hypertrophic chondrocytes are normal
• at E18.5, mice fail to exhibit bone deposition in the perichondrium flanking the hypertrophic regions where the bone collar normally forms in the long bones in wild-type mice


Mouse Genome Informatics
cx13
    Ihhtm1Amc/Ihhtm1Amc
Shhtm1Chg/Shhtm1Chg

involves: 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
embryogenesis
• yolk sacs are essentially avascular
• embryos is in primitive unturned position at E9.5
• yolk sacs are thin and transparent
• at E9.5 yolk sac mesoderm is a thin lining of inner yolk sac surface whick adheres to mesodermal layer of amnion in some embryos

cardiovascular system
• yolk sacs are essentially avascular