Mouse Models for the Dissection of CHD7 Functions in Eye Development and the Molecular Basis for Ocular Defects in CHARGE Syndrome - PubMed (original) (raw)
Mouse Models for the Dissection of CHD7 Functions in Eye Development and the Molecular Basis for Ocular Defects in CHARGE Syndrome
Philip J Gage et al. Invest Ophthalmol Vis Sci. 2015 Dec.
Abstract
Purpose: CHARGE syndrome (Coloboma of the eye, Heart defects, Atresia of the choanae, Retardation of growth and/or development, Genital and/or urinary tract abnormalities, and Ear abnormalities and deafness) is the second-leading cause of deaf-blindness after Usher syndrome. Heterozygous mutations in CHD7 cause CHARGE syndrome in 70% to 90% of patients. We tested the hypothesis that tissue-specific mutant mice provide models for molecularly dissecting CHD7 functions during eye development.
Methods: The conditional Chd7flox allele was mated together with tissue-specific Cre transgenes. Immunohistochemistry was used to determine the normal CHD7 pattern in the early eye primordia and to assess Chd7 mutants for expression of region-specific protein markers.
Results: CHD7 is present in the neural ectoderm and surface ectoderm of the eye. Deletion from neural and surface ectoderm results in severely dysmorphic eyes generally lacking recognizable optic cup structures and small lenses. Deletion from the neural ectoderm results in similar defects. Deletion from the surface ectoderm results in eyes with smaller lenses. Lens tissue and the major subdivisions of the neural ectoderm are present following conditional deletion of Chd7 from the neural ectoderm. Closure of the optic fissure depends on the Chd7 gene dose within the neural ectoderm.
Conclusions: Eye development requires CHD7 in multiple embryonic tissues. Lens development requires CHD7 in the surface ectoderm, whereas optic cup and stalk morphogenesis require CHD7 in the neural ectoderm. CHD7 is not absolutely required for specification of the major subdivisions within the neural ectoderm. As in humans, normal eye development in mice is sensitive to Chd7 haploinsufficiency. These data indicate the Chd7 mutant mice are models for determining the molecular etiology of ocular defects in CHARGE syndrome.
Figures
Figure 1
CHD7 expression in surface and/or neural ectoderm is essential for early eye morphogenesis. CHD7 protein expression at the indicated stages was detected by immunohistochemistry (A–D). The Foxg1-Cre transgene was used to ablate Chd7 in both the surface and neural ectoderm, and eye morphogenesis in control (E–H) and conditional knockout embryos (CKO) (I–L) at the indicated stages was assessed following staining by H&E. CHD7 is expressed in both surface and neural ectoderm at all stages examined. Conditional ablation of Chd7 in both surface and neural ectoderm severely disrupts early eye morphogenesis, in extreme cases resulting in the total absence of any optic cup or lens structures. All images are taken from coronal sections and are oriented with dorsal at the top. ov, optic vesicle; se, surface ectoderm; oc, optic cup; lv, lens vesicle; r, retina; l, lens.
Figure 2
Tissue-specific ablation of Chd7 from surface versus neural ectoderm differentially affects early eye morphogenesis. The Le-Cre and Rx-Cre transgenes were used to ablate Chd7 specifically from the surface ectoderm (seko) (A–C) and neural ectoderm (neko) (D–F), respectively. Representative sections from e12.5 control and knockout embryos were imaged following staining by H&E. Tissue-specific ablation of Chd7 from the surface ectoderm resulted in moderate (B) to significant (C) reduction in lens size but normal-appearing development of the neural ectoderm, including the optic cup. Tissue-specific ablation of Chd7 from the neural ectoderm resulted in significant (E) to severe (F) dysmorphogenesis of the optic cup and significantly alterations in lens development. All images are taken from coronal sections and are oriented with dorsal at the top.
Figure 3
Heterozygous and homozygous neural ectoderm-specific Chd7 knockout embryos exhibit coloboma. The state of embryonic fissure closure in e12.5 control and neural ectoderm specific Chd7 knockout embryos was analyzed in whole mount (A–C) and in corresponding sagittal sections (A′–C′). Coloboma is uniformly present in both heterozygous and homozygous Chd7 neural ectoderm-specific mutants, and the defect is significantly more severe in homozygous embryos. Embryos and sections are oriented with anterior at the top.
Figure 4
CHD7 function in neural ectoderm is not required to specify lens tissue in the surface ectoderm. Immunohistochemistry against β-crystallin was used to assay for the presence of lens tissue in e12.5 control (A) and Chd7neko/neko embryos. Lens tissue was present in all Chd7neko/neko eyes examined. In most cases, small but distinct lenses are present (B) but, in the most severely affected eyes, lens tissue is limited to small patches of β-crystallin positive cells in the surface ectoderm (C, C′). All images are taken from coronal sections and are oriented with dorsal at the top.
Figure 5
Cell autonomous function of CHD7 is not required to specify major subdivisions within the neural ectoderm during early eye development. Immunohistochemistry was used on sections from e12.5 control and Chd7neko/neko embryos to test for specification of appropriate regions of neural ectoderm as optic stalk (PAX2), optic cup (PAX6), retina (VSX2), pigmented epithelium (MITF), and neurons (TUJ1). All four markers are expressed in mutant eyes. All images are taken from coronal sections and are oriented with dorsal at the top.
Similar articles
- CHD7 regulates cardiovascular development through ATP-dependent and -independent activities.
Yan S, Thienthanasit R, Chen D, Engelen E, Brühl J, Crossman DK, Kesterson R, Wang Q, Bouazoune K, Jiao K. Yan S, et al. Proc Natl Acad Sci U S A. 2020 Nov 17;117(46):28847-28858. doi: 10.1073/pnas.2005222117. Epub 2020 Oct 30. Proc Natl Acad Sci U S A. 2020. PMID: 33127760 Free PMC article. - Great vessel development requires biallelic expression of Chd7 and Tbx1 in pharyngeal ectoderm in mice.
Randall V, McCue K, Roberts C, Kyriakopoulou V, Beddow S, Barrett AN, Vitelli F, Prescott K, Shaw-Smith C, Devriendt K, Bosman E, Steffes G, Steel KP, Simrick S, Basson MA, Illingworth E, Scambler PJ. Randall V, et al. J Clin Invest. 2009 Nov;119(11):3301-10. doi: 10.1172/JCI37561. Epub 2009 Oct 12. J Clin Invest. 2009. PMID: 19855134 Free PMC article. - Distinct cerebellar foliation anomalies in a CHD7 haploinsufficient mouse model of CHARGE syndrome.
Whittaker DE, Kasah S, Donovan APA, Ellegood J, Riegman KLH, Volk HA, McGonnell I, Lerch JP, Basson MA. Whittaker DE, et al. Am J Med Genet C Semin Med Genet. 2017 Dec;175(4):n/a. doi: 10.1002/ajmg.c.31595. Epub 2017 Nov 23. Am J Med Genet C Semin Med Genet. 2017. PMID: 29168327 Free PMC article. - Clinical and molecular effects of CHD7 in the heart.
Corsten-Janssen N, Scambler PJ. Corsten-Janssen N, et al. Am J Med Genet C Semin Med Genet. 2017 Dec;175(4):487-495. doi: 10.1002/ajmg.c.31590. Epub 2017 Oct 31. Am J Med Genet C Semin Med Genet. 2017. PMID: 29088513 Review. - Molecular and phenotypic aspects of CHD7 mutation in CHARGE syndrome.
Zentner GE, Layman WS, Martin DM, Scacheri PC. Zentner GE, et al. Am J Med Genet A. 2010 Mar;152A(3):674-86. doi: 10.1002/ajmg.a.33323. Am J Med Genet A. 2010. PMID: 20186815 Free PMC article. Review.
Cited by
- CHARGE syndrome in a child with a CHD7 variant and a novel pathogenic SOX2 variant: A case report.
Kamimura M, Shima H, Suzuki E, Sogi C, Fujiwara I, Adachi M, Haruna H, Takubo N, Fukami M, Kikuchi A, Kanno J. Kamimura M, et al. Clin Pediatr Endocrinol. 2024 Oct;33(4):214-218. doi: 10.1297/cpe.2024-0006. Epub 2024 Jul 7. Clin Pediatr Endocrinol. 2024. PMID: 39359670 Free PMC article. - Deletion of the chd7 Hinders Oligodendrocyte Progenitor Cell Development and Myelination in Zebrafish.
Shi L, Wang Z, Li Y, Song Z, Yin W, Hu B. Shi L, et al. Int J Mol Sci. 2023 Aug 31;24(17):13535. doi: 10.3390/ijms241713535. Int J Mol Sci. 2023. PMID: 37686337 Free PMC article. - Pervasive cortical and white matter anomalies in a mouse model for CHARGE syndrome.
Donovan APA, Rosko L, Ellegood J, Redhead Y, Green JBA, Lerch JP, Huang JK, Basson MA. Donovan APA, et al. J Anat. 2023 Jul;243(1):51-65. doi: 10.1111/joa.13856. Epub 2023 Mar 13. J Anat. 2023. PMID: 36914558 Free PMC article. - Craniofacial and cardiac defects in chd7 zebrafish mutants mimic CHARGE syndrome.
Sun Y, Kumar SR, Wong CED, Tian Z, Bai H, Crump JG, Bajpai R, Lien CL. Sun Y, et al. Front Cell Dev Biol. 2022 Dec 7;10:1030587. doi: 10.3389/fcell.2022.1030587. eCollection 2022. Front Cell Dev Biol. 2022. PMID: 36568983 Free PMC article. - Chromatin remodeler Chd7 regulates photoreceptor development and outer segment length.
Krueger LA, Bills JD, Lim ZY, Skidmore JM, Martin DM, Morris AC. Krueger LA, et al. Exp Eye Res. 2023 Jan;226:109299. doi: 10.1016/j.exer.2022.109299. Epub 2022 Nov 4. Exp Eye Res. 2023. PMID: 36343670 Free PMC article.
References
- Chow RL,, Lang RA. Early eye development in vertebrates. Annu Rev Cell Dev Biol. 2001; 17: 255–296. - PubMed
- Harris J,, Robert E,, Kallen B. Epidemiology of choanal atresia with special reference to the CHARGE association. Pediatrics. 1997; 99: 363–367. - PubMed
- Issekutz KA,, Graham JM,, Jr,, Prasad C,, Smith IM,, Blake KD., et al. An epidemiological analysis of CHARGE syndrome: preliminary results from a Canadian study. Am J Med Genet Part A. 2005; 133A: 309–317. - PubMed
Publication types
MeSH terms
Substances
Grants and funding
- EY007003/EY/NEI NIH HHS/United States
- EY014126/EY/NEI NIH HHS/United States
- R01 EY014126/EY/NEI NIH HHS/United States
- R01 DC009410/DC/NIDCD NIH HHS/United States
- DC009410/DC/NIDCD NIH HHS/United States
- P30 DC005188/DC/NIDCD NIH HHS/United States
- P30 EY007003/EY/NEI NIH HHS/United States
- F31 EY007003/EY/NEI NIH HHS/United States
LinkOut - more resources
Full Text Sources
Other Literature Sources
Molecular Biology Databases
Research Materials