Analysis of the role of BMP signaling in early eye development
Kalaskar, Vijay Kumar
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Bone morphogenetic proteins (BMP) and their receptors are expressed in ocular tissue during the stages of early eye specification and development, and are required for normal eye development. Recent screening of individuals with ocular malformations revealed mutations in the gene locus of one of the BMP members, BMP4. Compared to other BMP members, BMP4 expression is more predominant in ocular tissues during development. Understanding the role of BMP4 has been difficult as BMP4-/- homozygous mouse embryos die at mid-gestation, precluding the study of BMP4 in early eye development. However, co-culture studies revealed that BMP4 signaling in the optic vesicle was essential for its lens inducing activity. Although BMP4 is expressed at later stages, its role in mammalian eye development following lens induction is not clear. My dissertation research was directed towards elucidating the role of BMP signaling in mammalian eye development. To circumvent the problems associated with embryonic lethality, I developed a mouse embryo culture system capable of supporting eye development in a manner consistent with that observed in utero. I manipulated BMP signaling utilizing both gain and loss of function approaches through ectopic expression of BMP4 and Noggin proteins, respectively. I showed that BMP signaling plays several separable roles in eye development including specification, patterning and development. In cultured mouse embryos, ectopic BMP4 prevented development of pigmentation in retinal pigmented epithelium (RPE) through down-regulation of genes involved in RPE specification and development such as Mitf, Otx2 and Pax6. In neural retina (NR), ectopic BMP4 altered expression of genes involved in dorsal-ventral patterning, such as Tbx2, Tbx5, Msx1 and Vax2, and down-regulated the expression of genes involved in NR specification and development, including Vsx2, Pax6, Sox2, Rx and Lhx2. In contrast, loss of BMP signaling resulted in upregulation of genes such as Mitf and Pax6 and changed the expression domains of genes involved in dorsal-ventral patterning. Further analysis revealed that BMP signaling mediated these effects on NR and RPE by modulating the members of WNT and SHH signaling pathways. My results suggest a predominant role for BMP signaling in regulating the mechanisms important in NR and RPE specification and development.