transforming-growth-factor-beta and Coloboma

Colobomata are etiologically heterogeneous and may occur as an isolated defect or as a feature of a variety of single-gene disorders, chromosomal syndromes, or malformation syndromes. Although not classically associated with Marfan syndrome, colobomata have been described in several reports of Marfan syndrome, typically involving the lens and rarely involving other ocular structures. While colobomata of the lens have been described in Marfan syndrome, there are very few reports of coloboma involving other ocular structures. We report a newborn boy presenting with coloboma of the iris, lens, retina, and optic disk who was subsequently diagnosed with Marfan syndrome. Marfan syndrome is a disorder of increased TGFβ signaling, and recent work in the mouse model suggests a role for TGFβ signaling in eye development and coloboma formation, suggesting a causal association between Marfan syndrome and coloboma.

Topics: Adult; Arachnodactyly; Coloboma; DNA Mutational Analysis; Female; Fibrillins; Gestational Age; Humans; Infant, Newborn; Iris; Lens, Crystalline; Male; Marfan Syndrome; Microfilament Proteins; Mutation; Optic Disk; Retina; Signal Transduction; Transforming Growth Factor beta

Smad7 is an intracellular inhibitory protein that antagonizes the signaling of TGF-β family members. Deletion of Smad7 in the mouse leads to an abnormality in heart development. However, whether Smad7 has a functional role in the development of other organs has been elusive. Here we present evidence that Smad7 imparts a role to eye development in the mouse. Smad7 is expressed in both the lens and retina in the developing embryonic eye. Depletion of Smad7 caused various degrees of coloboma and microphthalmia with alterations in cell apoptosis and proliferation in eyes. Smad7 was implicated in lens differentiation but was not required for the induction of the lens placode. The development of the periocular mesenchyme was retarded with the down-regulation of Bmp7 and Pitx2 in mutant mice. Retinal spatial patterning was affected by Smad7 deletion and was accompanied by altered bone morphogenetic protein (BMP) signaling. At late gestation stages, TGF-β signaling was up-regulated in the differentiating retina. Smad7 mutant mice displayed an expanded optic disc with increasing of sonic hedgehog (SHH) signaling. Furthermore, loss of Smad7 led to a temporal change in retinal neurogenesis. In conclusion, our study suggests that Smad7 is essential for eye development. In addition, our data indicate that alterations in the signaling of BMP, TGF-β, and SHH likely underlie the defects in eye development caused by Smad7 deletion.

Topics: Animals; Bone Morphogenetic Protein 7; Cell Differentiation; Coloboma; Down-Regulation; Gene Deletion; Hedgehog Proteins; Homeobox Protein PITX2; Homeodomain Proteins; Lens, Crystalline; Mice; Mice, Mutant Strains; Microphthalmos; Neurogenesis; Retina; Signal Transduction; Smad7 Protein; Transcription Factors; Transforming Growth Factor beta

We describe that Sox11, a member of the group C of the Sox transcription factor family, is critically required during the morphogenetic processes of early eye development, and that lack of Sox11 results in ocular anterior segment dysgenesis (ASD). Sox11-deficient mice show a persistent lens stalk, a delay in lens formation, and the phenotypes of Peters' anomaly and microphthalmia at birth. In addition, the optic fissure does not close in the anterior halves of the eyes resulting in anterior coloboma. The delay in lens formation is associated with a reduced mitotic activity in the lens placode during its invagination into the optic cup. No changes in Pax6 expression are observed in the developing eyes of Sox11-/- mice, whereas the expression of Sox11 is reduced in optic cup, optic vesicle and lens placode of Pax6+/- embryos and in the optic vesicle of Pax6-/- mice. Transfection experiments show an increase in Sox11 expression when higher doses of Pax6 are present. Considerably smaller amounts of BMP7 are expressed in lens and optic cup of Sox11-/- mice as compared to their wild-type littermates. We conclude that Sox11 is required during separation of the lens vesicle from the surface ectoderm and the closure of the anterior optic fissure. The expression of Sox11 in early eye development is under control of Pax6, and changes in BMP7-signalling appear to be involved in the effects of Sox11 on anterior eye development. Our findings suggest that SOX11 might similarly be involved in the pathogenesis of ASD in human patients.

Topics: Animals; Anterior Eye Segment; Blotting, Western; Bone Morphogenetic Protein 7; Bone Morphogenetic Proteins; Coloboma; Eye Proteins; Fetal Development; High Mobility Group Proteins; Homeodomain Proteins; Lens, Crystalline; Mice; Mice, Inbred C57BL; Microphthalmos; Mitosis; Paired Box Transcription Factors; PAX6 Transcription Factor; Repressor Proteins; RNA, Messenger; SOXC Transcription Factors; Transforming Growth Factor beta

During early formation of the eye, the optic vesicle becomes partitioned into a proximal domain that forms the optic nerve and a distal domain that forms the retina. In this study, we investigate the activity of Nodal, Hedgehog (Hh) and Fgf signals and Vax family homeodomain proteins in this patterning event. We show that zebrafish vax1 and vax2 are expressed in overlapping domains encompassing the ventral retina, optic stalks and preoptic area. Abrogation of Vax1 and Vax2 activity leads to a failure to close the choroid fissure and progressive expansion of retinal tissue into the optic nerve, finally resulting in a fusion of retinal neurons and pigment epithelium with forebrain tissue. We show that Hh signals acting through Smoothened act downstream of the Nodal pathway to promote Vax gene expression. However, in the absence of both Nodal and Hh signals, Vax genes are expressed revealing that other signals, which we show include Fgfs, contribute to Vax gene regulation. Finally, we show that Pax2.1 and Vax1/Vax2 are likely to act in parallel downstream of Hh activity and that the bel locus (yet to be cloned) mediates the ability of Hh-, and perhaps Fgf-, signals to induce Vax expression in the preoptic area. Taking all these results together, we present a model of the partitioning of the optic vesicle along its proximo-distal axis.

Topics: Animals; Body Patterning; Coloboma; Eye Proteins; Gene Expression Regulation; Gene Expression Regulation, Developmental; Genes, Homeobox; Hedgehog Proteins; Homeodomain Proteins; Humans; In Situ Hybridization; Neuropeptides; Nodal Protein; Optic Nerve; Phylogeny; Receptors, Cell Surface; Receptors, Fibroblast Growth Factor; Receptors, G-Protein-Coupled; Recombinant Fusion Proteins; Retina; Signal Transduction; Smoothened Receptor; Trans-Activators; Transforming Growth Factor beta; Xenopus Proteins; Zebrafish; Zebrafish Proteins