Haploinsufficiency of Six3 Fails to Activate Sonic hedgehog Expression in the Ventral Forebrain and Causes Holoprosencephaly

Xin Geng, Christina Speirs, Oleg Lagutin, Adi Inbal, Wei Liu, Lilianna Solnica-Krezel, Yongsu Jeong, Douglas J. Epstein, Guillermo Oliver*

*Corresponding author for this work

Research output: Contribution to journalArticlepeer-review

149 Scopus citations


Holoprosencephaly (HPE), the most common forebrain malformation, is characterized by an incomplete separation of the cerebral hemispheres. Mutations in the homeobox gene SIX3 account for 1.3% of all cases of human HPE. Using zebrafish-based assays, we have now determined that HPE-associated Six3 mutant proteins function as hypomorphs. Haploinsufficiency of Six3 caused by deletion of one allele of Six3 or by replacement of wild-type Six3 with HPE-associated Six3 mutant alleles was sufficient to recapitulate in mouse models most of the phenotypic features of human HPE. We demonstrate that Shh is a direct target of Six3 in the rostral diencephalon ventral midline (RDVM). Reduced amounts of functional Six3 protein fail to activate Shh expression in the mutant RDVM and ultimately lead to HPE. These results identify Six3 as a direct regulator of Shh expression and reveal a crossregulatory loop between Shh and Six3 in the ventral forebrain.

Original languageAmerican English
Pages (from-to)236-247
Number of pages12
JournalDevelopmental Cell
Issue number2
StatePublished - 12 Aug 2008
Externally publishedYes

Bibliographical note

Funding Information:
We thank C. Chiang and S.K. McConnell for the Shh +/− and Bf1-Cre mouse strains, respectively. For plasmids, we thank S. Aizawa, R. Grosschedl, J. L. Rubenstein, Q. Ma, A. McMahon, P. Gruss, P. McKinnon, and B.L. Hogan. We also thank L. Zhang for confocal imaging, L. Boykins for scanning electron microscopy, Y. Lee for technical support with real-time PCR, R.S. Srinivasan and A. Lavado for critical reading of this manuscript, and A. McArthur for editing the manuscript. This project was supported in part by National Institutes of Health grants R01 NS052386 (to G.O. and L.S.K.) and R01 NS39421 (to D.J.E.), Cancer Center Support CA-21765 (G.O.), R01 NS39421 (D.E.), the American Lebanese Syrian Associated Charities, and Vanderbilt University Zebrafish Initiative Academic Venture Capital Fund (AVCF).




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