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Distinct roles of Central missing and Dispatched in sending the Hedgehog signal
1Center for Developmental Biology and Department of Pharmacology, University of Texas Southwestern Medical Center, Dallas, Texas 75390-9133, USA.
Insights
Researchers identified central missing (cmn), a novel protein regulating the Hedgehog (Hh) signaling pathway. Cmn acts independently of cholesterol modification, unlike other pathway components, and is crucial for Hh signal transduction in development.
Area of Science:
- Developmental Biology
- Molecular Biology
- Genetics
Background:
- Secreted Hedgehog (Hh) proteins are crucial for animal development, controlling growth and patterning.
- The precise mechanisms of Hh signal secretion and transduction remain incompletely understood.
Purpose of the Study:
- To identify novel positive regulators of the Hedgehog (Hh) signaling pathway through a genetic screen.
- To characterize the function and mechanism of a newly discovered pathway component.
Main Methods:
- Conducted a genetic screen to identify regulators of the Hh pathway.
- Analyzed new alleles of known genes (hh, dispatched) and a novel gene (central missing - cmn).
- Investigated the effects of cmn loss-of-function mutations on Hh pathway gene expression and signaling.
Main Results:
- Identified a novel Hh pathway component, central missing (cmn), through genetic screening.
- cmn loss-of-function mutations phenocopy hh and dispatched (disp) mutations, affecting patterning.
- cmn acts upstream of patched (ptc) in Hh-secreting cells and regulates Hh activity independently of cholesterol modification.
- cmn mutations map to CG11495, encoding a membrane-bound acyltransferase similar to Porcupine.
Conclusions:
- Central missing (cmn) is a novel, essential regulator of the Hedgehog (Hh) signaling pathway.
- cmn functions in Hh-secreting cells, upstream of patched, and its role is independent of cholesterol modification.
- cmn represents a new class of Hh pathway regulators, potentially involved in acyltransferase activity related to signal secretion.
Abstract:
Secreted Hedgehog (Hh) proteins control many aspects of growth and patterning in animal development. The mechanism by which the Hh signal is sent and transduced is still not well understood. We describe a genetic screen aimed at identifying positive regulators in the hh pathway. We recovered multiple new alleles of hh and dispatched (disp). In addition, we identified a novel component in the hh pathway, which we name central missing (cmn). Loss-of-function mutations in cmn cause similar patterning defects to those caused by hh or dispatched (disp) mutations. Moreover, cmn affects the expression of hh responsive genes but not of hh itself. Like disp, cmn acts upstream of patched (ptc) and its activity is required only in the Hh secreting cells. However, unlike disp, which is required for the release of the cholesterol-modified form of Hh, cmn regulates the activity of Hh in a manner that is independent of cholesterol modification. Finally, we show that cmn mutations bear molecular lesions in CG11495, which encodes a putative membrane bound acyltransferase related to Porcupine, a protein implicated in regulating the secretion of Wingless (Wg) signal.