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PMID: 19286674 Published · ppublish English Journal Article Research Support, N.I.H., Extramural Research Support, Non-U.S. Gov't

Tubby-like protein 3 (TULP3) regulates patterning in the mouse embryo through inhibition of Hedgehog signaling.

Human molecular genetics ·Vol. 18 ·No. 10 ·2009-05-15 ·Pages 1740-54

Norman RX, Ko HW, Huang V, Eun CM, Abler LL, Zhang Z, Sun X, Eggenschwiler JT

Abstract

Tubby-like protein 3 (TULP3) is required for proper embryonic development in mice. Disruption of mouse Tulp3 results in morphological defects in the embryonic craniofacial regions, the spinal neural tube and the limbs. Here, we show that TULP3 functions as a novel negative regulator of Sonic hedgehog (Shh) signaling in the mouse. In Tulp3 mutants, ventral cell types in the lumbar neural tube, which acquire their identities in response to Shh signaling, are ectopically specified at the expense of dorsal cell types. Genetic epistasis experiments show that this ventralized phenotype occurs independently of Shh and the transmembrane protein Smoothened, but it is dependent on the transcription factor Gli2. The ventralized phenotype is also dependent on the kinesin II subunit Kif3A, which is required for intraflagellar transport and ciliogenesis. In addition, TULP3 is required for proper Shh-dependent limb patterning and for maintaining the correct balance between differentiation and proliferation in the neural tube. Finally, the localization of TULP3 to the tips of primary cilia raises the possibility that it regulates the Hedgehog pathway within this structure.

MeSH Terms
Animals Body Patterning Down-Regulation Embryo, Mammalian Embryonic Development Female Gene Expression Regulation, Developmental Hedgehog Proteins/genetics,metabolism Humans Intercellular Signaling Peptides and Proteins Intracellular Signaling Peptides and Proteins Male Mice Mice, Inbred C3H Mice, Transgenic Mutation Neural Tube/embryology,metabolism Proteins/genetics,metabolism Signal Transduction Spinal Cord/embryology,metabolism
Chemicals
Hedgehog Proteins Intercellular Signaling Peptides and Proteins Intracellular Signaling Peptides and Proteins Proteins Shh protein, mouse Tulp3 protein, mouse
Authors & Affiliations
8 authors, click to expand affiliations / ORCID
Norman Ryan X
Department of Molecular Biology, Princeton University, Princeton, NJ 08544, USA.
Ko Hyuk W
Huang Viola
Eun Christine M
Abler Lisa L
Zhang Zhen
Sun Xin
Eggenschwiler Jonathan T
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Article Info
Journal
Human molecular genetics
Abbr.
Hum Mol Genet
ISSN
1460-2083
DOI
10.1093/hmg/ddp113
Published
2009-05-15
Epub
2009-00-12
Pages
1740-54
Language
English
Region
England
NLM ID
9208958
PMCID
PMC2671991
Subset
IM
Grants
NICHD NIH HHS · R01 HD050761 · United States
NICHD NIH HHS · HD050761 · United States
NICHD NIH HHS · HD045522 · United States
External Links
PubMed source DOI: 10.1093/hmg/ddp113 PMC Full Text View journal details
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