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SOX2 hypomorphism disrupts development of the prechordal floor and optic cup.

ABSTRACT: Haploinsufficiency for the HMG-box transcription factor SOX2 results in abnormalities of the human ventral forebrain and its derivative structures. These defects include anophthalmia (absence of eye), microphthalmia (small eye) and hypothalamic hamartoma (HH), an overgrowth of the ventral hypothalamus. To determine how Sox2 deficiency affects the morphogenesis of the ventral diencephalon and eye, we generated a Sox2 allelic series (Sox2(IR), Sox2(LP), and Sox2(EGFP)), allowing for the generation of mice that express germline hypomorphic levels (<40%) of SOX2 protein and that faithfully recapitulate SOX2 haploinsufficient human phenotypes. We find that Sox2 hypomorphism significantly disrupts the development of the posterior hypothalamus, resulting in an ectopic protuberance of the prechordal floor, an upregulation of Shh signaling, and abnormal hypothalamic patterning. In the anterior diencephalon, both the optic stalks and optic cups (OC) of Sox2 hypomorphic (Sox2(HYP)) embryos are malformed. Furthermore, Sox2(HYP) eyes exhibit a loss of neural potential and coloboma, a common phenotype in SOX2 haploinsufficient humans that has not been described in a mouse model of SOX2 deficiency. These results establish for the first time that germline Sox2 hypomorphism disrupts the morphogenesis and patterning of the hypothalamus, optic stalk, and the early OC, establishing a model of the development of the abnormalities that are observed in SOX2 haploinsufficient humans.

SUBMITTER: Langer L

PROVIDER: S-EPMC4077342 | biostudies-literature | 2012 Mar-Jun

REPOSITORIES: biostudies-literature

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SOX2 hypomorphism disrupts development of the prechordal floor and optic cup.

Langer Lee L Taranova Olena O Sulik Kathleen K Pevny Larysa L

Mechanisms of development 20120301 1-4

Haploinsufficiency for the HMG-box transcription factor SOX2 results in abnormalities of the human ventral forebrain and its derivative structures. These defects include anophthalmia (absence of eye), microphthalmia (small eye) and hypothalamic hamartoma (HH), an overgrowth of the ventral hypothalamus. To determine how Sox2 deficiency affects the morphogenesis of the ventral diencephalon and eye, we generated a Sox2 allelic series (Sox2(IR), Sox2(LP), and Sox2(EGFP)), allowing for the generation ...[more]

PMID: 22522080

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Project description:In the early embryo, the eyes form initially as relatively spherical optic vesicles (OVs) that protrude from both sides of the brain tube. Each OV grows until it contacts and adheres to the overlying surface ectoderm (SE) via an extracellular matrix (ECM) that is secreted by the SE and OV. The OV and SE then thicken and bend inward (invaginate) to create the optic cup (OC) and lens vesicle, respectively. While constriction of cell apices likely plays a role in SE invagination, the mechanisms that drive OV invagination are poorly understood. Here, we used experiments and computational modeling to explore the hypothesis that the ECM locally constrains the growing OV, forcing it to invaginate. In chick embryos, we examined the need for the ECM by (1) removing SE at different developmental stages and (2) exposing the embryo to collagenase. At relatively early stages of invagination (Hamburger-Hamilton stage HH14[Formula: see text]), removing the SE caused the curvature of the OV to reverse as it 'popped out' and became convex, but the OV remained concave at later stages (HH15) and invaginated further during subsequent culture. Disrupting the ECM had a similar effect, with the OV popping out at early to mid-stages of invagination (HH14[Formula: see text] to HH14[Formula: see text]). These results suggest that the ECM is required for the early stages but not the late stages of OV invagination. Microindentation tests indicate that the matrix is considerably stiffer than the cellular OV, and a finite-element model consisting of a growing spherical OV attached to a relatively stiff layer of ECM reproduced the observed behavior, as well as measured temporal changes in OV curvature, wall thickness, and invagination depth reasonably well. Results from our study also suggest that the OV grows relatively uniformly, while the ECM is stiffer toward the center of the optic vesicle. These results are consistent with our matrix-constraint hypothesis, providing new insight into the mechanics of OC (early retina) morphogenesis.

Dataset Information

SOX2 hypomorphism disrupts development of the prechordal floor and optic cup.

Publications

SOX2 hypomorphism disrupts development of the prechordal floor and optic cup.

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