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Eye Development and Gene Expression Shiva Swamynathan [email protected] Why study eye development & gene expression? Opaque Cornea Iridocorneal Fusion Keratolenticular Fusion Peters Anomaly FOXC1, PAX6, PITX2, or CYP1B1 Anophthalmia SOX2 Microphthalmia PAX6, OTX2, CHX10 & RAX Aniridia PAX6 Anophthalmia RAX Axenfeld-Rieger Syndrome PITX2 Cell lineage during vertebrate eye development Drosophila eye transcriptome transcription factor genes are highly expressed Structural and pigment biosynthesis genes genes involved in intracellular signaling, neurotransmission, and the visual process Transcription factor network that establishes the eye field Whitney Heavner and Larysa Pevny. 2012. Cold Spring Harb Perspect Biol 2012;4:a008391 Gene expression in the developing optic vesicle Transcription factors regulating corneal development Swamynathan, S.K. 2013. J. Ophthalmol. 103947. PMID: 23533700 Mature cornea is formed by 8-10 weeks after birth E12.5 E17.5 E14.5 E18.5 E16.5 Adult Number of differentially regulated genes in the cornea between different time points Stephens et al 2013. J. Bio. Chem. 288:34304-24 Cornea derives cells from the surface ectoderm and neural crest mesenchyme Swamynathan, S.K. 2013. J. Ophthalmol. 103947. PMID: 23533700 Transcription Factors in the Mouse Cornea Highly expressed in the cornea KLF4 IRF1 ELF3 Ets homologous factor HEB KLF5 JunB Rev-erbA-a IRF6 Oxysterols receptor LXR-b Pax6 Norman et al. 2004. IOVS. 45: 429-40 PMID: 14744882 Functions of Klf4 and Klf5 in the ocular surface Wild Type Klf4CN Wild Type Klf5CN Swamynathan et al., 2007. Mol. Cell. Biol. 27:182-194 Kenchegowda et al 2011. Dev. Biol. 356:5-18 Gene, transcript and protein structure of Pax6 Pax6 regulatory networks during early eye development Neuroectoderm lineage Surface ectoderm lineage Pax6 is essential for normal corneal development Ramaesh et al., 2005. Exp.Eye Res. 81: 224-35 Corneal functions of Pax6 are dosage-dependent Mort et al. 2011. PMID: 22220198 Role of Pitx2 in corneal development Paired-like homeodomain transcription factor PITX2 in E14.5 P42 PITX2 Mutants Overabundance of mesenchyme Malformed stroma and endothelium Absence of anterior chamber Corneo-lenticular fusion Gage et al. 2014. Dev Dyn. PMID: 25044936 Pitx2 helps establish corneal avascularity Gage et al. 2014. Dev Dyn. PMID: 25044936 Corneal epithelium and the lens are both derived from the head surface ectoderm Surface Ectoderm forms the Lens & the Corneal Epithelium Lens and Cornea Share Transcriptional Networks Genetic pathways inducing lens differentiation Pax6 and Sox2 cooperatively regulate chicken δ1-crystallin gene expression Kamachi et al 2001. Genes Dev. 15: 1272-86 Sox2 regulates cell-specific target genes through distinct partner factors Kamachi et al 2001. Genes Dev. 15: 1272-86 Organization of retinal circuits Transcription factors regulating temporal progression of mouse retinogenesis Whitney Heavner and Larysa Pevny. 2012. Cold Spring Harb Perspect Biol 2012;4:a008391 Stages of photoreceptor development OTX2 plays an essential role in vertebrate retinogenesis Otx2 expression in developing retina Otx2-/- WT Otx2-/- WT E12.5 E17.5 PN6 PN 0 Otx2-/- WT PN 9 Temporal functions of Otx2 in the mouse retina OTX2 mutations are associated with blinding ocular defects and brain abnormalities OTX2 gene network in the developing retina Xenopus Mouse Xenopus Xenopus Rx expression, phenotypes and regulation Xenopus Human overexpression Essential roles of LHX2 in eye development • Lhx2 is a LIM domain (a double-zinc finger motif found in a variety of proteins)containing homeobox gene expressed in B-cells, forebrain and neural retina • LHX2 coregulates the expression of Pax6, Six3 and Rax in the optic vesicle • LHX2 is essential for eye development Human NRL gene and protein Nrl is required for rod photoreceptor development Optic vesicle and RPE specification MITF: A big gene associated with small eyes Summary • Large-scale expression studies suggest that about a thousand genes are expressed in a preferential manner in the eye, compared with the rest of the body • A series of homeobox transcription factors including Otx2, Sox2, Lhx2, Rax and Pax6 play a major role in different stages of eye development • Eyefield is specified in early embryos by overlapping expression of Otx2 and Sox2 in the neural ectoderm, which in turn activate expression of Lhx2, Rax and Pax6, resulting in the formation of the optic vesicle • Inductive interaction between neural ectoderm and surface ectoderm results in formation of the lens placode, defined by the expression of Pax6 and Sox2 • Lens and cornea share many transcriptional networks, consistent with their origin from the surface ectoderm • Pitx2 and Foxc1 play major roles in anterior segment formation • Sox2 regulates cell-specific target genes by cooperating with distinct factors such as Pax6, Oct3/4 and Brn2 • Pax6 plays a major role in early retinogenesis, and formation of lens and cornea. • Cone cells are the default photoreceptor cell type. NRL expression is essential for rod cell formation • Mitf plays a critical role in RPE formation Expression of homeobox genes in the mature vertebrate retina