JAX
Mouse Strain Datasheet - 004290
129-Ihhtm1Amc/J
Also Known As: Ihh KO
These Ihh knock-out mice exhibit embryonic lethality that may be due to circulatory abnormalities.
Donating Investigator
Andrew P McMahon, University of Southern California
Genetic overview
| Genetic Background | Generation |
|---|---|
|
|
Ihhtm1Amc
| Allele Type | Gene Symbol | Gene Name |
|---|---|---|
| Targeted (Null/Knockout) | Ihh | Indian hedgehog |
Detailed Description
Mice that are heterozygous for the targeted allele are viable and fertile. Mice homozygous for this mutation have a lethal phenotype. Half of homozygous null mice have an embryonic lethal phenotype, dying between 10.5 to 12.5 days post coitum. The cause of embryonic death may be due to circulatory abnormalities. Embryonic death also occurred in late gestation, with the remaining homozygous mutants dying at birth, due to respiratory failure. At 12.5 dpc, initial cartilaginous primordia of mutant embryos forelimbs are not abnormal, but by 13.5 dpc, mutant embryos display severe foreshortening of the forelimbs. At birth, the length of long bones of mutant animals are only one third the length of long bones of wildtype animals. Mutants have reduced chondrocyte proliferation, abnormal chondrocyte maturation and absence of mature osteoblasts in endochondral bones. Recent studies have linked mutations of Ihh to brachydactyly type A-1 St-Jacques. This mutant mouse strain represents a model that may be useful in studies of skeletal morphogenesis.
Development
A targeting vector containing neomycin resistance and herpes simplex virus thymidine kinase genes was used to replace the entire first exon, encoding much of the signaling peptide, and approximately 1kb of flanking sequence. The construct was electroporated into 129 derived R1 embryonic stem (ES) cells. Correctly targeted ES cells were injected into C57BL/6 derived blastocysts. The resulting chimeric animals were backcrossed to 129X1 mice.
Control Suggestions
Selected References
- St-Jacques B; Hammerschmidt M; McMahon AP. 1999. Indian hedgehog signaling regulates proliferation and differentiation of chondrocytes and is essential for bone formation [published erratum appears in Genes Dev 1999 Oct 1;13(19):2617] Genes Dev 13(16):2072-86. PubMed: 10465785MGI: J:57297
Ihhtm1Amc
Allele Symbol: Ihhtm1Amc
| Allele Name | targeted mutation 1, Andrew P McMahon |
|---|---|
| Allele Type | Targeted (Null/Knockout) |
| Allele Synonym(s) | Ihh-; Ihhn |
| Gene Symbol and Name | Ihh, Indian hedgehog |
| Gene Synonym(s) | BDA1; HHG2 |
| Strain of Origin | (129X1/SvJ x 129S1/Sv)F1-Kitl<+> |
| Chromosome | 1 |
| Molecular Note | A neomycin resistance cassette replaced the entire first exon, which encodes much of the signaling peptide, and approximately 1kb of flanking sequence. |
| Mutations Made By | Andrew McMahon, University of Southern California |
Disease Terms
Research Areas By Genotype
This mouse can be used to support research in many areas including:
Genotype: Ihhtm1Amc related
- Developmental Biology Research
- Embryonic Lethality (Homozygous)
- incomplete
- Perinatal Lethality
- Homozygous
- Embryonic Lethality (Homozygous)
Mammalian Phenotype Terms by Genotype
Genotype: Ihhtm1Amc/Ihhtm1Amc
involves: 129S1/Sv * 129X1/SvJ
growth/size/body region phenotype
- decreased body height
- at birth, homozygotes are consistently shorter than wild-type mice (MGI Ref ID J:57297)
- disproportionate dwarf
- at birth mutants display severe short-limb dwarfism (MGI Ref ID J:89228)
- short snout
- at birth, homozygotes show a foreshortened snout (MGI Ref ID J:57297)
skeleton phenotype
- abnormal axial skeleton morphology
- (MGI Ref ID J:57297)
- abnormal bone mineralization
- 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 (MGI Ref ID J:57297)
- 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 (MGI Ref ID J:57297)
- abnormal bone ossification
- in homozygotes, appendicular skeletal elements fail to ossify (MGI Ref ID J:57297)
- abnormal cartilage development
- 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 (MGI Ref ID J:57297)
- abnormal chondrocyte morphology
- decrease in chondrocyte proliferation at E14.5 (MGI Ref ID J:73071)
- 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 (MGI Ref ID J:57297)
- premature chondrocyte hypertrophy, resulting in depletion of non-mineralized cartilage at articular ends of long bones (MGI Ref ID J:73071)
- abnormal humerus morphology
- abnormal joint morphology
- at 18.5 dpc, homozygotes show abnormal joint formation (MGI Ref ID J:57297)
- abnormal long bone epiphyseal plate proliferative zone
- 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 (MGI Ref ID J:57297)
- abnormal long bone morphology
- depletion of non-mineralized cartilage at articular ends of long bones (MGI Ref ID J:73071)
- 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 (MGI Ref ID J:57297)
- abnormal rib morphology
- mutant ribs do not display excessive calcification (MGI Ref ID J:57297)
- abnormal skeleton development
- skeletal growth retardation (MGI Ref ID J:73071)
- abnormal skeleton morphology
- 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 (MGI Ref ID J:57297)
- abnormal trabecular bone morphology
- 18.5 dpc, mutant humeri display no identifiable trabecular bone in the primary spongiosa (MGI Ref ID J:57297)
- chondrodystrophy
- reduced chondrocyte proliferation and severe short-limb dwarfism are seen (MGI Ref ID J:89228)
- decreased length of long bones
- at birth, mutant long bones are one-third the length of wild-type long bones (MGI Ref ID J:57297)
- decreased osteoblast cell number
- 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 (MGI Ref ID J:57297)
- in contrast, mature osteoblasts are present in mutant bones formed by intramembranous ossification (e.g. flat bones of the skull, mandible, and clavicle) (MGI Ref ID J:57297)
- decreased width of hypertrophic chondrocyte zone
- at 13.5 dpc, mutant humeri show absence of typical hypertrophic chondrocytes (MGI Ref ID J:57297)
- 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 (MGI Ref ID J:57297)
- such hypertrophic cells are surrounded by less mature chondrocytes and show no signs of vascularization or cortical bone formation (MGI Ref ID J:57297)
- delayed endochondral bone ossification
- domed cranium
- at birth, homozygotes show a rounded skull (MGI Ref ID J:57297)
- fused carpal bones
- at 18.5 dpc, some of the wrist bones of homozygotes appear partly fused (MGI Ref ID J:57297)
- short fibula
- (MGI Ref ID J:73071)
- short humerus
- (MGI Ref ID J:73071)
- short mandible
- at birth, homozygotes display a foreshortened mandible (MGI Ref ID J:57297)
- short ribs
- homozygotes have significantly shortened ribs (MGI Ref ID J:57297)
- short scapula
- length of scapula is shorter (MGI Ref ID J:73071)
- short tibia
- growth retardation of tibia (MGI Ref ID J:73071)
- short ulna
- (MGI Ref ID J:73071)
limbs/digits/tail phenotype
- abnormal digit morphology
- abnormal forelimb morphology
- at 13.5 dpc, homozygotes display visibly shortened forelimbs (MGI Ref ID J:57297)
- abnormal humerus morphology
- fused carpal bones
- at 18.5 dpc, some of the wrist bones of homozygotes appear partly fused (MGI Ref ID J:57297)
- short fibula
- (MGI Ref ID J:73071)
- short humerus
- (MGI Ref ID J:73071)
- short limbs
- short tail
- (MGI Ref ID J:57297)
- short tibia
- growth retardation of tibia (MGI Ref ID J:73071)
- short ulna
- (MGI Ref ID J:73071)
vision/eye phenotype
- vision/eye phenotype
mortality/aging
- embryonic lethality during organogenesis, incomplete penetrance
- neonatal lethality, complete penetrance
- homozygotes that develop to term die at birth due to respiratory failure (MGI Ref ID J:57297)
craniofacial phenotype
- domed cranium
- at birth, homozygotes show a rounded skull (MGI Ref ID J:57297)
- short mandible
- at birth, homozygotes display a foreshortened mandible (MGI Ref ID J:57297)
- short snout
- at birth, homozygotes show a foreshortened snout (MGI Ref ID J:57297)
respiratory system phenotype
- respiratory failure
- (MGI Ref ID J:57297)
The following phenotype information is associated with a similar, but not exact match to this JAX® Mice strain
Genotype: Ihhtm1Amc/Ihh+
involves: 129S1/Sv * 129X1/SvJ * C57BL/6
skeleton phenotype
- decreased long bone epiphyseal plate size
- modest shortening of the growth plate (MGI Ref ID J:99641)
Genotype: Ihhtm1Amc/Ihhtm1Amc
involves: 129S1/Sv * 129X1/SvJ * C57BL/6J * CBA/J
digestive/alimentary phenotype
- abnormal digestive organ placement
- at 18.5 dpc, all homozygotes display an obvious malrotation of the gut, in the absence of reversions in gut situs (MGI Ref ID J:62158)
- abnormal digestive system morphology
- at 18.5 dpc, homozygotes display a smaller gastrointestinal tract relative to wild-type (MGI Ref ID J:62158)
- abnormal duodenum morphology
- abnormal small intestine morphology
- at 18.5 dpc, homozygotes show a 34% reduction in thickness of the circular smooth muscle layer along the small intestine (MGI Ref ID J:62158)
- at 18.5 dpc, homozygotes show a significant dilation of the small intestine (MGI Ref ID J:62158)
- 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 (MGI Ref ID J:62158)
- aganglionic megacolon
- at 18.5 dpc, 50% of homozygotes display an aganglionic megacolon (MGI Ref ID J:62158)
- digestive/alimentary phenotype
- at 18.5 dpc, homozygotes exhibit no intestinal transformation of the stomach epithelium (MGI Ref ID J:62158)
- megacolon
- at 18.5 dpc, homozygotes display a significant dilation of parts of the colon as well as a thin wall (MGI Ref ID J:62158)
growth/size/body region phenotype
- decreased fetal size
- at 18.5 dpc, mutant embryos have an overall reduced size relative to wild-type embryos (MGI Ref ID J:62158)
nervous system phenotype
- absent enteric neurons
- at 18.5 dpc, enteric neurons are completely absent along parts of the small intestine and in dilated portions of the colon (MGI Ref ID J:62158)
endocrine/exocrine gland phenotype
- annular pancreas
- at 18.5 dpc, 43% of homozygotes exhibit an annular pancreas (MGI Ref ID J:62158)
muscle phenotype
- abnormal smooth muscle morphology
- at 18.5 dpc, homozygotes show a 34% reduction in thickness of the circular smooth muscle layer along the small intestine (MGI Ref ID J:62158)
Genotype: Ihhtm1Amc/Ihhtm1Amc
involves: 129S1/Sv * 129X1/SvJ * C57BL/6
embryo phenotype
- abnormal visceral yolk sac morphology
- (MGI Ref ID J:128367)
- abnormal vitelline vasculature morphology
- yolk sacs have fewer and thinner blood vessels compared to wild-type at E9.5 (MGI Ref ID J:128367)
cardiovascular system phenotype
- abnormal vitelline vasculature morphology
- yolk sacs have fewer and thinner blood vessels compared to wild-type at E9.5 (MGI Ref ID J:128367)
References
- St-Jacques B; Hammerschmidt M; McMahon AP. 1999. Indian hedgehog signaling regulates proliferation and differentiation of chondrocytes and is essential for bone formation [published erratum appears in Genes Dev 1999 Oct 1;13(19):2617] Genes Dev 13(16):2072-86. PubMed: 10465785MGI: J:57297
Additional - Ihhtm1Amc related
- Astorga J; Carlsson P. 2007. Hedgehog induction of murine vasculogenesis is mediated by Foxf1 and Bmp4. Development 134(20):3753-61. PubMed: 17881493MGI: J:128367
- Bondurand N; Southard-Smith EM. 2016. Mouse models of Hirschsprung disease and other developmental disorders of the enteric nervous system: Old and new players. Dev Biol 417(2):139-57. PubMed: 27370713MGI: J:235629
- Bren-Mattison Y; Hausburg M; Olwin BB. 2011. Growth of limb muscle is dependent on skeletal-derived Indian hedgehog. Dev Biol 356(2):486-95. PubMed: 21683695MGI: J:175458
- Capurro MI; Li F; Filmus J. 2009. Overgrowth of a mouse model of Simpson-Golabi-Behmel syndrome is partly mediated by Indian hedgehog. EMBO Rep 10(8):901-7. PubMed: 19590577MGI: J:157333
- Chen MH; Li YJ; Kawakami T; Xu SM; Chuang PT. 2004. Palmitoylation is required for the production of a soluble multimeric Hedgehog protein complex and long-range signaling in vertebrates. Genes Dev 18(6):641-59. PubMed: 15075292MGI: J:89228
- Colnot C; de la Fuente L; Huang S; Hu D; Lu C; St-Jacques B; Helms JA. 2005. Indian hedgehog synchronizes skeletal angiogenesis and perichondrial maturation with cartilage development. Development 132(5):1057-67. PubMed: 15689378MGI: J:97179
- Dakubo GD; Mazerolle C; Furimsky M; Yu C; St-Jacques B; McMahon AP; Wallace VA. 2008. Indian hedgehog signaling from endothelial cells is required for sclera and retinal pigment epithelium development in the mouse eye. Dev Biol 320(1):242-55. PubMed: 18582859MGI: J:139168
- Dakubo GD; Wang YP; Mazerolle C; Campsall K; McMahon AP; Wallace VA. 2003. Retinal ganglion cell-derived sonic hedgehog signaling is required for optic disc and stalk neuroepithelial cell development. Development 130(13):2967-80. PubMed: 12756179MGI: J:83530
- Ehlen H. 2013. Inactivation of anoctamin-6/Tmem16f, a regulator of phosphatidylserine scrambling in osteoblasts, leads to decreased mineral deposition in skeletal tissues J Bone Miner Res 28(2):246-59. PubMed: 22936354MGI: J:195901
- Gao B; Hu J; Stricker S; Cheung M; Ma G; Law KF; Witte F; Briscoe J; Mundlos S; He L; Cheah KS; Chan D. 2009. A mutation in Ihh that causes digit abnormalities alters its signalling capacity and range. Nature 458(7242):1196-200. PubMed: 19252479MGI: J:147878
- Hebrok M; Kim SK; St Jacques B; McMahon AP; Melton DA. 2000. Regulation of pancreas development by hedgehog signaling. Development 127(22):4905-13. PubMed: 11044404MGI: J:65293
- Hojo H; Ohba S; Taniguchi K; Shirai M; Yano F; Saito T; Ikeda T; Nakajima K; Komiyama Y; Nakagata N; Suzuki K; Mishina Y; Yamada M; Konno T; Takato T; Kawaguchi H; Kambara H; Chung UI. 2013. Hedgehog-Gli activators direct osteo-chondrogenic function of bone morphogenetic protein toward osteogenesis in the perichondrium. J Biol Chem 288(14):9924-32. PubMed: 23423383MGI: J:197832
- Hojo H; Ohba S; Yano F; Saito T; Ikeda T; Nakajima K; Komiyama Y; Nakagata N; Suzuki K; Takato T; Kawaguchi H; Chung UI. 2012. Gli1 protein participates in Hedgehog-mediated specification of osteoblast lineage during endochondral ossification. J Biol Chem 287(21):17860-9. PubMed: 22493482MGI: J:185618
- Hu H; Hilton MJ; Tu X; Yu K; Ornitz DM; Long F. 2005. Sequential roles of Hedgehog and Wnt signaling in osteoblast development. Development 132(1):49-60. PubMed: 15576404MGI: J:94274
- Huang AH; Riordan TJ; Pryce B; Weibel JL; Watson SS; Long F; Lefebvre V; Harfe BD; Stadler HS; Akiyama H; Tufa SF; Keene DR; Schweitzer R. 2015. Musculoskeletal integration at the wrist underlies the modular development of limb tendons. Development 142(14):2431-41. PubMed: 26062940MGI: J:224077
- Joeng KS; Long F. 2009. The Gli2 transcriptional activator is a crucial effector for Ihh signaling in osteoblast development and cartilage vascularization. Development 136(24):4177-85. PubMed: 19906844MGI: J:154905
- Karp SJ; Schipani E; St-Jacques B; Hunzelman J; Kronenberg H; McMahon AP. 2000. Indian hedgehog coordinates endochondral bone growth and morphogenesis via parathyroid hormone related-protein-dependent and -independent pathways. Development 127(3):543-8. PubMed: 10631175MGI: J:59287
- Kesper DA; Didt-Koziel L; Vortkamp A. 2010. Gli2 activator function in preosteoblasts is sufficient to mediate Ihh-dependent osteoblast differentiation, whereas the repressor function of Gli2 is dispensable for endochondral ossification. Dev Dyn 239(6):1818-26. PubMed: 20503377MGI: J:160585
- Kobayashi T; Soegiarto DW; Yang Y; Lanske B; Schipani E; McMahon AP; Kronenberg HM. 2005. Indian hedgehog stimulates periarticular chondrocyte differentiation to regulate growth plate length independently of PTHrP. J Clin Invest 115(7):1734-42. PubMed: 15951842MGI: J:99641
- Koyama E; Ochiai T; Rountree RB; Kingsley DM; Enomoto-Iwamoto M; Iwamoto M; Pacifici M. 2007. Synovial joint formation during mouse limb skeletogenesis: roles of Indian hedgehog signaling. Ann N Y Acad Sci 1116:100-12. PubMed: 18083924MGI: J:133905
- Koziel L; Wuelling M; Schneider S; Vortkamp A. 2005. Gli3 acts as a repressor downstream of Ihh in regulating two distinct steps of chondrocyte differentiation. Development 132(23):5249-60. PubMed: 16284117MGI: J:102948
- Lenton K; James AW; Manu A; Brugmann SA; Birker D; Nelson ER; Leucht P; Helms JA; Longaker MT. 2011. Indian hedgehog positively regulates calvarial ossification and modulates bone morphogenetic protein signaling. Genesis 49(10):784-96. PubMed: 21557453MGI: J:178364
- Levi B; James AW; Nelson ER; Brugmann SA; Sorkin M; Manu A; Longaker MT. 2011. Role of Indian hedgehog signaling in palatal osteogenesis. Plast Reconstr Surg 127(3):1182-90. PubMed: 21364421MGI: J:182649
- Li X; Blagden CS; Bildsoe H; Bonnin MA; Duprez D; Hughes SM. 2004. Hedgehog can drive terminal differentiation of amniote slow skeletal muscle. BMC Dev Biol 4:9. PubMed: 15238161MGI: J:107621
- Liu C; Peng J; Matzuk MM; Yao HH. 2015. Lineage specification of ovarian theca cells requires multicellular interactions via oocyte and granulosa cells. Nat Commun 6:6934. PubMed: 25917826MGI: J:222787
- Long F; Joeng KS; Xuan S; Efstratiadis A; McMahon AP. 2006. Independent regulation of skeletal growth by Ihh and IGF signaling. Dev Biol 298(1):327-33. PubMed: 16905129MGI: J:119575
- Long F; Zhang XM; Karp S; Yang Y; McMahon AP. 2001. Genetic manipulation of hedgehog signaling in the endochondral skeleton reveals a direct role in the regulation of chondrocyte proliferation. Development 128(24):5099-108. PubMed: 11748145MGI: J:73071
- Mao J; Kim BM; Rajurkar M; Shivdasani RA; McMahon AP. 2010. Hedgehog signaling controls mesenchymal growth in the developing mammalian digestive tract. Development 137(10):1721-9. PubMed: 20430747MGI: J:160363
- Nelson ER; Levi B; Sorkin M; James AW; Liu KJ; Quarto N; Longaker MT. 2011. Role of GSK-3beta in the osteogenic differentiation of palatal mesenchyme. PLoS One 6(10):e25847. PubMed: 22022457MGI: J:179587
- Outram SV; Hager-Theodorides AL; Shah DK; Rowbotham NJ; Drakopoulou E; Ross SE; Lanske B; Dessens JT; Crompton T. 2009. Indian hedgehog (Ihh) both promotes and restricts thymocyte differentiation. Blood 113(10):2217-28. PubMed: 19109233MGI: J:145997
- Ramalho-Santos M; Melton DA; McMahon AP. 2000. Hedgehog signals regulate multiple aspects of gastrointestinal development. Development 127(12):2763-72. PubMed: 10821773MGI: J:62158
- Shibukawa Y; Young B; Wu C; Yamada S; Long F; Pacifici M; Koyama E. 2007. Temporomandibular joint formation and condyle growth require Indian hedgehog signaling. Dev Dyn 236(2):426-34. PubMed: 17191253MGI: J:117221
- Tu X; Joeng KS; Long F. 2012. Indian hedgehog requires additional effectors besides Runx2 to induce osteoblast differentiation. Dev Biol 362(1):76-82. PubMed: 22155527MGI: J:180304
- Wang YP; Dakubo G; Howley P; Campsall KD; Mazarolle CJ; Shiga SA; Lewis PM; McMahon AP; Wallace VA. 2002. Development of normal retinal organization depends on Sonic hedgehog signaling from ganglion cells. Nat Neurosci 5(9):831-2. PubMed: 12195432MGI: J:78708
- Witte F; Chan D; Economides AN; Mundlos S; Stricker S. 2010. Receptor tyrosine kinase-like orphan receptor 2 (ROR2) and Indian hedgehog regulate digit outgrowth mediated by the phalanx-forming region. Proc Natl Acad Sci U S A 107(32):14211-6. PubMed: 20660756MGI: J:163602
- Young B; Minugh-Purvis N; Shimo T; St-Jacques B; Iwamoto M; Enomoto-Iwamoto M; Koyama E; Pacifici M. 2006. Indian and sonic hedgehogs regulate synchondrosis growth plate and cranial base development and function. Dev Biol 299(1):272-82. PubMed: 16935278MGI: J:171806
- Zhang XM; Ramalho-Santos M; McMahon AP. 2001. Smoothened mutants reveal redundant roles for Shh and Ihh signaling including regulation of L/R symmetry by the mouse node. Cell 106(2):781-92. PubMed: 11517919MGI: J:175111
- Zhang XQ; Afink GB; Hu XR; Nister M; Forsberg-Nilsson K. 2005. Gli1 is not required for Pdgfralpha expression during mouse embryonic development. Differentiation 73(2-3):109-19. PubMed: 15811134MGI: J:97242