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Identification of Inositol Phosphate or Phosphoinositide Interacting Proteins by Affinity Chromatography Coupled to Western Blot or Mass Spectrometry
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Identification of Inositol Phosphate or Phosphoinositide Interacting Proteins by Affinity Chromatography Coupled to Western Blot or Mass Spectrometry

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INPP5E regulates phosphoinositide-dependent cilia transition zone function

Jennifer M Dyson1, Sarah E Conduit1, Sandra J Feeney1

  • 1Cancer Program, Monash Biomedicine Discovery Institute and Department of Biochemistry and Molecular Biology, Monash University, Clayton, Victoria 3800, Australia.

The Journal of Cell Biology
|December 22, 2016
PubMed

Insights

Inositol polyphosphate 5-phosphatase INPP5E is crucial for cilia function and embryonic development. Its absence disrupts Hedgehog signaling, leading to ciliopathies like Joubert syndrome.

Area of Science:

  • Cell Biology
  • Developmental Biology
  • Genetics

Background:

  • Human ciliopathies, such as Joubert syndrome (JBTS), stem from cilia dysfunction.
  • The inositol polyphosphate 5-phosphatase INPP5E, mutated in JBTS, localizes to cilia, but its precise role is under investigation.
  • Inpp5e knockout mice exhibit JBTS-like phenotypes, including embryonic lethality and developmental defects.

Purpose of the Study:

  • To elucidate the function of INPP5E at cilia and its role in Hedgehog signaling.
  • To investigate the molecular mechanisms underlying Inpp5e deficiency-induced ciliopathy phenotypes.

Main Methods:

  • Utilized mouse genetics to study Inpp5e knockout embryos.
  • Analyzed Hedgehog signaling pathways and cilia function in Inpp5e-deficient cells.
  • Investigated the localization and function of INPP5E using wild-type and mutant forms.

Main Results:

  • Inpp5e knockout embryos displayed aberrant Hedgehog signaling and developmental defects.
  • Increased Hedgehog signaling partially rescued ciliopathy phenotypes in Inpp5e knockout mice.
  • Absence of INPP5E led to phosphoinositide accumulation at the cilia transition zone (TZ), impairing TZ protein recruitment and Smoothened levels.
  • Restoration of INPP5E function normalized TZ organization and Smoothened localization.

Conclusions:

  • INPP5E is essential for maintaining cilia transition zone function and regulating Hedgehog signaling during embryonic development.
  • INPP5E acts as a critical link between phosphoinositide metabolism and Hedgehog signaling at the cilia.
  • Dysfunctional INPP5E contributes to ciliopathies by disrupting cilia signaling pathways.

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