Expression of the homeobox gene Pitx2 in neural crest is required for optic stalk and ocular anterior segment development

Abstract

Heterozygous mutations in the homeobox gene, PITX2, result in ocular anterior segment defects and a high incidence of early-onset glaucoma. Pitx2 is expressed in both the neural crest and the mesoderm-derived precursors of the periocular mesenchyme. Complete loss of function in mice results in agenesis or severe disruption of periocular mesenchyme structures and extrinsic defects in early optic nerve development. However, the specific requirements for Pitx2 in neural crest versus mesoderm could not be determined using these mice, and only roles in the initial stages of eye development could be assessed due to early embryonic lethality. To determine the specific roles of Pitx2 in the neural crest precursor pool, we generated neural crest-specific Pitx2 knockout mice (Pitx2-ncko). Because Pitx2-nkco mice are viable, we also analyzed gene function in later eye development. Pitx2 is intrinsically required in neural crest for specification of corneal endothelium, corneal stroma and the sclera. Pitx2 function in neural crest is also required for normal development of ocular blood vessels. Pitx2-ncko mice exhibit a unique optic nerve phenotype in which the eyes are progressively displaced towards the midline until they are directly attached to the ventral hypothalamus. As Pitx2 is not expressed in the optic stalk, an essential function of PITX2 protein in neural crest is to regulate an extrinsic factor(s) required for development of the optic nerve. We propose a revised model of optic nerve development and new mechanisms that may underlie the etiology of glaucoma in Axenfeld-Rieger patients.

The differentiation and morphogenesis of craniofacial muscles

“…Our own studies have suggested that pitx2 regulates myogenic cell number cell autonomously, consistent with its ability to regulate cell proliferation in the satellite cell line, C2C12 (Kioussi et al, 2002;Francis-West, unpublished data). This has been confirmed recently by the demonstration that gene-inactivation of pitx2 in the periocular cranial neural crest cell does not affect the early differentiation of eye muscles (Evans and Gage, 2005).…”

Cranial muscle defects of Pitx2 mutants result from specification defects in the first branchial arch

“…Pitx2 is strongly expressed in muscle (15), neural crest (20)(21)(22), cardiac fields (23) (C.K., unpublished data) and brain cell lineages (29). Mutants of the Pitx2 homeobox gene have phenotypes in body parts corresponding to each of the gene's embryonic expression domains.…”

“…These Pitx2 ϩ /myogenin Ϫ cells may be either surface ectoderm or neural crest derivatives. Pitx2 expression in neural crest derivatives has also been observed in other regions of the head (20)(21)(22)(23). Pitx2 expression was generally not observed in nonmyogenic territories surrounding anlagen in other regions of the body (17) Severe losses in myogenin ϩ /Pitx2 ϩ territories were observed in the region adjacent to the tongue that represents the vestigial jaw ( Fig.…”

Case of novel PITX2 gene mutation associated with Peters' anomaly and persistent hyperplastic primary vitreous

“…2 This hypothesis is consistent with recent findings that PITX2 expression in neural crest cells is observed not only in the anterior segment but also in the vitreous cavity at embryonic day 12.5 in mice. 3 Moreover, the deletion of 6p25, on which FOXC1 is located, which has a functional link with PITX2, 4 was reported to be associated with PHPV and Axenfeld-Rieger syndrome, 5 a syndrome thought to present the same spectrum of defects as Peters' anomaly.…”