# Understanding how ciliary gene mutations affect the processing and activity of Gli2 and Gli3 transcription factors

> **NIH NIH R01** · WEILL MEDICAL COLL OF CORNELL UNIV · 2021 · $366,629

## Abstract

Abstract
 The primary cilium is a solitary microtubule-based organelle that protrudes from the cell surface and is
found on most vertebrate cells. It serves as a sensory organelle in organs such as the kidney and retina and
also functions in transducing extracellular signals such as Hedgehog (Hh), a secreted signaling molecule that
is essential for embryo development and cell proliferation and differentiation. Defects in cilia structure and
function are associated with a diverse array of developmental abnormalities, collectively termed “ciliopathies”.
 Hh signaling in vertebrates occurs in primary cilia and is primarily mediated by Gli2 and Gli3 zinc finger-
containing transcription factors. Gli2 is primarily an activator, whereas Gli3 is mostly a repressor, though it also
exhibits a weak activator function. Consistent with their functions, most full-length Gli3 (Gli3FL) is proteolytically
processed to generate a C-terminally truncated repressor in the absence of Hh signaling, while only a small
fraction of Gli2FL is processed. Gli2/Gli3 processing is induced by phosphorylation of the first four of the six
serine/threonine residues at their C-termini by protein kinase A (PKA) and then by glycogen synthase kinase 3
(GSK3) and casein kinase 1 (CK1). The multi-phosphorylated Gli2/Gli3 are then ubiquitinated and partially
degraded by the proteasome. Hh signaling inhibits Gli2/Gli3 processing by suppressing PKA-mediated
phosphorylation of the first four PKA sites and also activates Gli2FL/Gli3FL by inhibiting the phosphorylation of
the fifth and sixth PKA sites in their C-termini.
 Defects in cilia structure and function mostly affect Hh signaling. One near universal hallmark of ciliary
gene mutants at the molecular level is the reduced Gli2/Gli3 processing. Interestingly, however, the levels of
Gli2/Gli3 activity in ciliary gene mutants vary from none to elevated depending on mutated ciliary genes. This
suggests that the mechanism by which ciliary proteins regulate Hh signaling is diverse and complex. While the
effect of ciliary mutations on Hh signaling is well established, the molecular mechanisms underlying these
effects are thus far unknown. The goal of this proposal is to elucidate the molecular mechanisms by which
Gli2/Gli3 processing, stability, and activity are altered in ciliary gene mutants.

## Key facts

- **NIH application ID:** 10296258
- **Project number:** 1R01GM140115-01A1
- **Recipient organization:** WEILL MEDICAL COLL OF CORNELL UNIV
- **Principal Investigator:** BAOLIN WANG
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2021
- **Award amount:** $366,629
- **Award type:** 1
- **Project period:** 2021-07-01 → 2025-04-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10296258

## Citation

> US National Institutes of Health, RePORTER application 10296258, Understanding how ciliary gene mutations affect the processing and activity of Gli2 and Gli3 transcription factors (1R01GM140115-01A1). Retrieved via AI Analytics 2026-05-22 from https://api.ai-analytics.org/grant/nih/10296258. Licensed CC0.

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