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Mutations in mouse Ift144 model the craniofacial, limb and rib defects in skeletal ciliopathies

Alyson Ashe1, Natalie C Butterfield, Liam Town

  • 1Epigenetics Laboratory, Queensland Institute for Medical Research, Herston, Queensland 4006, Australia.

Human Molecular Genetics
|January 10, 2012
PubMed

Insights

Mutations in the IFT144 gene cause skeletal and craniofacial defects in ciliopathies. A new mouse model, Ift144(twt), mimics these human conditions, revealing insights into hedgehog signaling pathways.

Area of Science:

  • Genetics
  • Developmental Biology
  • Cell Biology

Background:

  • Ciliopathies are genetic disorders linked to defects in primary cilia, often manifesting as skeletal dysplasia.
  • Mutations in intraflagellar transport (IFT) genes, particularly IFT-A, are implicated in human ciliopathies like Sensenbrenner and Jeune syndromes.
  • IFT144 is a key component of the IFT-A complex, crucial for cilia assembly and function.

Purpose of the Study:

  • To characterize a novel mouse mutant with a hypomorphic mutation in the Ift144 gene.
  • To investigate the role of IFT144 in skeletal and craniofacial development and its impact on signaling pathways.
  • To establish an allelic series of Ift144 mutants for studying ciliopathies.

Main Methods:

  • Generation and phenotypic analysis of the N-ethyl-N-nitrosourea-induced mouse mutant Ift144(twt).
  • Examination of skeletal and craniofacial anomalies in mutant embryos.
  • Analysis of hedgehog (Hh) signaling pathway activity and ciliogenesis in Ift144 mutant cells.
  • Assessment of limb outgrowth in embryos with different Ift144 alleles.

Main Results:

  • The Ift144(twt) mouse mutant exhibits skeletal and craniofacial defects mirroring human ciliopathies.
  • Mutant embryos show ligand-independent expansion of Hh signaling despite defective ciliogenesis.
  • Phenotypes include polydactyly, cleft palate, and abnormal rib development, suggesting complex signaling pathway involvement.
  • A dose-dependent effect on limb outgrowth was observed, consistent with short-limb phenotypes.

Conclusions:

  • The Ift144(twt) mouse model effectively recapitulates key features of human skeletal ciliopathies.
  • Defects in IFT144 impact ciliogenesis and lead to dysregulated Hh signaling, contributing to developmental anomalies.
  • The study highlights the critical role of IFT144 in skeletal development and provides a valuable resource for further research into ciliopathies.

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