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Human Molecular Genetics Advance Access published online on April 27, 2007
Human Molecular Genetics, doi:10.1093/hmg/ddm096
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© The Author 2007. Published by Oxford University Press. All rights reserved. For Permissions, please email: journals.permissions@oxfordjournals.org

Ectopic sonic hedgehog signaling impairs telencephalic dorsal midline development: implication for human holoprosencephaly

Xi Huang, Ying Litingtung and Chin Chiang*

Department of Cell and Developmental Biology, Vanderbilt University Medical Center, 4114 MRB III, Nashville, TN 37232

* Address all correspondence to: Chin Chiang, Ph.D, chin.chiang{at}vanderbilt.edu, Tel: (615) 343-4922, Fax: (615) 936-3475

Received December 15, 2006; Revised April 11, 2007; Accepted April 11, 2007

Holoprosencephaly (HPE) is the most common developmental anomaly of the human forebrain, and in its severe form, the cerebral hemispheres fail to completely separate into two distinct halves. Although disruption of ventral forebrain induction is thought to underlie most HPE cases, a subset of HPE patients exhibits preferential dysgenesis of forebrain dorsal midline structures with unknown etiology. In this study, we show that Sonic hedgehog (Shh) lacking cholesterol moiety in one allele (ShhN/+) in mice can elicit ectopic Shh signaling in early telencephalon to induce ventral progenitor marker expression in the cortical region and impair telencephalic dorsal midline development. Prolonged ectopic ShhN signaling impaired Bmp and Wnt signalings from the dorsal patterning center through upregulation of Fgf8, leading to augmented cell proliferation, decreased cell death and impaired roof plate morphogenesis. Accordingly, ShhN/+ mutant telencephalic dorsal midline structures, including cortical hem, hippocampus and choroid plexus, either failed to form or were hypoplastic. Strikingly, ShhN/+ mutants displayed a spectrum of phenotypic features such as failure of anterior cerebral hemisphere to divide, hydrocephalus and cleft palate which have been observed in a human patient with milder HPE predicted to produce SHHN protein due to a truncation mutation in one SHH allele. We propose that elevated ectopic Shh signaling can impair dorsal telencephalic midline morphogenesis, and lead to non-cleavage of midline structures mimicking human HPE with dorsal midline defects.


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X. Huang, T. Ketova, J. T. Fleming, H. Wang, S. K. Dey, Y. Litingtung, and C. Chiang
Sonic hedgehog signaling regulates a novel epithelial progenitor domain of the hindbrain choroid plexus
Development, August 1, 2009; 136(15): 2535 - 2543.
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