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Human Molecular Genetics Advance Access published online on February 17, 2009
Human Molecular Genetics, doi:10.1093/hmg/ddp075
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© 2009 The Author(s)
This is an Open Access article distributed under the terms of the Creative Commons Attribution Non-Commercial License (http://creativecommons.org/licenses/by-nc/2.0/uk/) which permits unrestricted non-commercial use, distribution, and reproduction in any medium, provided the original work is properly cited.

Mouse hitchhiker mutants have spina bifida, dorso-ventral patterning defects and polydactyly: Identification of Tulp3 as a novel negative regulator of the Sonic hedgehog pathway

Victoria L. Patterson1, Christine Damrau1, Anju Paudyal1, Benjamin Reeve1, Daniel T. Grimes1, Michelle E. Stewart2, Debbie J. Williams1, Pam Siggers1, Andy Greenfield1 and Jennifer N. Murdoch1,*

1 Mammalian Genetics Unit 2 Mary Lyon Centre MRC Harwell Harwell Science and Innovation Campus OXON OX11 0RD UK

* Author for correspondence; MRC Harwell, Mammalian Genetics Unit, Harwell Science and Innovation Campus, OXON OX11 0RD, UK; Email: J.Murdoch{at}har.mrc.ac.uk; Tel: 01235 841381; Fax: 01235 841200

Received December 19, 2008; Revised February 6, 2009; Accepted February 12, 2009

The mammalian sonic hedgehog (Shh) signalling pathway is essential for embryonic development and the patterning of multiple organs. Disruption or activation of Shh signalling leads to multiple birth defects, including holoprosencephaly, neural tube defects and polydactyly, and in adults results in tumours of the skin or central nervous system. Genetic approaches with model organisms continue to identify novel components of the pathway, including key molecules that function as positive or negative regulators of Shh signalling. Data presented here define Tulp3 as a novel negative regulator of the Shh pathway. We have identified a new mouse mutant that is a strongly hypomorphic allele of Tulp3 and which exhibits expansion of ventral markers in the caudal spinal cord, as well as neural tube defects and preaxial polydactyly, consistent with increased Shh signalling. We demonstrate that Tulp3 acts genetically downstream of Shh and Smoothened (Smo) in neural tube patterning and exhibits a genetic interaction with Gli3 in limb development. We show that Tulp3 does not appear to alter expression or processing of Gli3, and we demonstrate that transcriptional regulation of other negative regulators (Rab23, Fkbp8, Thm1, Sufu and PKA) is not affected. We discuss the possible mechanism of action of Tulp3 in Shh-mediated signalling in light of these new data.


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