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.
| Original language | English |
|---|---|
| Pages (from-to) | 1740-1754 |
| Number of pages | 15 |
| Journal | Human Molecular Genetics |
| Volume | 18 |
| Issue number | 10 |
| DOIs | |
| Publication status | Published - 2009 May 7 |
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All Science Journal Classification (ASJC) codes
- Genetics
- Genetics(clinical)
- Molecular Biology
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Tubby-like protein 3 (TULP3) regulates patterning in the mouse embryo through inhibition of Hedgehog signaling. / Norman, Ryan X.; Ko, Hyuk W.; Huang, Viola; Eun, Christine M.; Abler, Lisa L.; Zhang, Zhen; Sun, Xin; Eggenschwiler, Jonathan T.
In: Human Molecular Genetics, Vol. 18, No. 10, 07.05.2009, p. 1740-1754.Research output: Contribution to journal › Article
TY - JOUR
T1 - Tubby-like protein 3 (TULP3) regulates patterning in the mouse embryo through inhibition of Hedgehog signaling
AU - Norman, Ryan X.
AU - Ko, Hyuk W.
AU - Huang, Viola
AU - Eun, Christine M.
AU - Abler, Lisa L.
AU - Zhang, Zhen
AU - Sun, Xin
AU - Eggenschwiler, Jonathan T.
PY - 2009/5/7
Y1 - 2009/5/7
N2 - 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.
AB - 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.
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U2 - 10.1093/hmg/ddp113
DO - 10.1093/hmg/ddp113
M3 - Article
VL - 18
SP - 1740
EP - 1754
JO - Human Molecular Genetics
JF - Human Molecular Genetics
SN - 0964-6906
IS - 10
ER -