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Gli proteins encode context-dependent positive and negative functions: implications for development and disease.

A Ruiz i Altaba1

  • 1The Skirball Institute, Developmental Genetics Program and Department of Cell Biology, NYU School of Medicine, New York, NY 10016, USA. ria@saturn.med.nyu.edu

Development (Cambridge, England)
|June 22, 1999
PubMed
Summary

Zinc finger Gli proteins interpret Hedgehog signals. C-terminal truncations impact function, linking Gli3 to human syndromes and revealing context-dependent roles in development and disease.

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Area of Science:

  • Molecular Biology
  • Developmental Biology
  • Genetics

Background:

  • The Gli family of zinc finger proteins are key mediators of Hedgehog (Hh) signaling, crucial for normal development and implicated in various diseases.
  • C-terminally truncated GLI3 proteins are associated with human syndromes, but their precise functional role compared to full-length proteins remains unclear.

Purpose of the Study:

  • To investigate the structure-function relationships of Gli proteins, particularly the role of C-terminal sequences in Hedgehog signaling.
  • To elucidate the mechanisms underlying the differential functions of Gli1, Gli2, and Gli3 proteins and their truncated forms.

Main Methods:

  • Structure-function analyses of Gli proteins were conducted using floor plate and neuronal induction assays in frog embryos.
  • Alkaline phosphatase (AP) induction assays in SHH-responsive mouse C3H10T1/2 cells were employed.

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  • Analyses included nuclear-targeted Gli proteins, tagged Gli cDNAs, and the effect of protein kinase A (PKA) on Gli function.

    • Main Results:

    • C-terminal sequences are essential for positive inducing activity and cytoplasmic localization of Gli proteins.
    • N-terminal sequences dictate dominant-negative function and nuclear localization.
    • C-terminally truncated GLI3 proteins contribute to Polydactyly type A and Pallister-Hall Syndrome phenotypes.
    • Gli1 mimics SHH in inducing AP activity, while full-length Gli3 and truncated forms act antagonistically; Gli2 is inactive in this specific assay.
    • Protein kinase A (PKA) promotes Gli3 repressor formation and inhibits Gli1 function, indicating context-dependent regulation.

    Conclusions:

    • Gli protein function exhibits context-dependent divergence, with distinct roles for Gli1, Gli2, and Gli3 in responding to Shh signaling.
    • The balance between activator and repressor forms of Gli proteins is critical for proper Hh signal interpretation.
    • Misregulation of Gli protein function, particularly the production of C-terminally truncated forms, has significant biological consequences and underlies certain human developmental disorders.