Abstract
Septo-optic dysplasia (SOD) is a congenital brain anomaly that results in pituitary, optic nerve, and midline forebrain defects. The etiology of SOD is poorly understood, with the majority of cases being sporadic. In rare instances, SOD is caused by mutations in Sox2, Sox3, or Hesx1, but how this manifests in disease is not entirely certain. We demonstrate here that mouse embryos lacking Sonic hedgehog (Shh) in the prospective hypothalamus exhibit key features of SOD, including pituitary hypoplasia and absence of the optic disc. The hypothalamic source of Shh is required to maintain gene expression boundaries along the anteroposterior and mediolateral neural axes that are important for proper pituitary and eye development, respectively. We further reveal that Sox2 and Sox3 are dose-dependent regulators of Shh transcription that directly bind and activate a long-range Shh forebrain enhancer. These data indicate that reduced levels of Shh expression in the hypothalamus cause SOD. Septo-optic dysplasia (SOD) is a congenital brain anomaly resulting in pituitary hormone deficiency and blindness. Zhao et al. reveal that reducing hypothalamic Sonic hedgehog (Shh) production causes SOD-like phenotypes in mice. Transcription factors mutated in human SOD patients regulate hypothalamic Shh expression, suggesting a unified model for the disorder.
| Original language | English |
|---|---|
| Pages (from-to) | 585-596 |
| Number of pages | 12 |
| Journal | Developmental Cell |
| Volume | 22 |
| Issue number | 3 |
| DOIs | |
| Publication status | Published - 13 Mar 2012 |
Bibliographical note
Funding Information:We thank Dr. Jean Richa and his staff at the University of Pennsylvania Transgenic and Mouse Chimeric Facility for their assistance in transgenic mouse production, as well as the staff at the Biological Services Section at the National Institute for Medical Research. We are grateful to Drs. Dan Kelberman and Mehul Dattani (University College London, London, UK) for kindly providing the human Sox2 expression constructs. We also thank Drs. Steve Liebhaber and Kenny Campbell for constructive comments on the manuscript. This work was supported by National Institutes of Health grant R01 NS039421 from the National Institute of Neurological Disorders and Stroke (to D.J.E.), March of Dimes grant 1-FY08-421 (to D.J.E.), and the MRC (U117512772 to K.R. and R.L.-B.).
