Academic journal article Genetics

A Screen for Modifiers of Hedgehog Signaling in Drosophila Melanogaster Identifies Swm and Mts

Academic journal article Genetics

A Screen for Modifiers of Hedgehog Signaling in Drosophila Melanogaster Identifies Swm and Mts

Article excerpt


Signaling by Hedgehog (Hh) proteins shapes most tissues and organs in both vertebrates and invertebrates, and its misregulation has been implicated in many human diseases. Although components of the signaling pathway have been identified, key aspects of the signaling mechanism and downstream targets remain to be elucidated. We performed an enhancer/suppressor screen in Drosophila to identify novel components of the pathway and identified 26 autosomal regions that modify a phenotypic readout of Hh signaling. Three of the regions include genes that contribute constituents to the pathway-patched, engrailed, and hh. One of the other regions includes the gene microtubule star (mts) that encodes a subunit of protein phosphatase 2A. We show that mts is necessary for full activation of Hh signaling. A second region includes the gene second mitotic wave missing (swm). swm is recessive lethal and is predicted to encode an evolutionarily conserved protein with RNA binding and Zn^sup +^ finger domains. Characterization of newly isolated alleles indicates that swm is a negative regulator of Hh signaling and is essential for cell polarity.

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HH signaling is essential to the development of many tissues and organs in both vertebrates and invertebrates, and it has important medical implications. hh was first identified as a gene that is required for segmentation of the Drosophila embryo (Nusslein- Volhard and Wieschaus 1980); subsequent studies have established roles at all developmental stages in a variety of cell types. When signaling is reduced in human, sheep, fish, and mouse embryos, severe holoprosencephaly and cyclopia result (Belloni et al. 1996; Chiang et al. 1996; Roessler et al. 1996; Schier et al. 1997). Increased signaling in human adults can lead to cancers of the skin, cerebellum, muscle, digestive tract, pancreas, and prostate (reviewed in Pasca DiMagliano and Hebrok 2003). Hh signaling is complex, and a complete understanding of Hh signaling will encompass the mechanism and regulation of active Hh protein production, its release from producing cells, its transit to target cells, the mechanism that senses its presence in target cells, and the output of the pathway on patterning and growth.

Synthesis of the mature Hh peptide involves multiple steps, including cleavage of a signal sequence from an inactive precursor, autoproteolysis, N-terminal palmitoylation, and C-terminal cholesteroylation (Porter et al. 1996; Pepinsky et al. 1998). The N-terminal lipid is essential for Hhactivity (Chamoun et al. 2001; Lee andTreisman 2001; Micchelli et al. 2002). The C-terminal cholesterol is needed to generate the normal distribution of transported protein (Porter et al. 1996; Gallet et al. 2003; Dawber et al. 2005; Callejo et al. 2006;Gallet et al. 2006). Release of lipid-modified Hh requires the Dispatched protein (Burke et al. 1999), but howDispatched interacts with and affectsHh awaits clarification. Movement of Hh away from producing cells may involve interactions with proteoglycans (reviewed in Eaton 2006) and may require assembly into a multimer form (Zeng et al. 2001; Chen et al. 2004; Feng et al. 2004; Gallet et al. 2006;).

In target cells, several membrane proteins contribute to the recognition of Hh- Patched (Ptc), Interference Hedgehog (Ihog), Brother of Ihog, and Smoothened (Smo) (Hooper 1994; Chen and Struhl 1996; Quirk et al. 1997; Yao et al. 2006). In the absence of Hh, Ptc inhibits Smo-dependent signal transduction. In the presence of Hh, Smo accumulates at the cell surface (Zhang et al. 2001, 2004; Apionishev et al. 2005; Lu et al. 2006) and binds through its intracellular C-terminal tail to a Hh signaling complex. Other constituents of this complex include the kinase Fused, (Fu), the kinesin-related motor protein Costal2 (Cos2), Suppressor of Fused (SuFu), and the Zn+ finger transcription factor Cubitus interruptus (Ci). It is thought that Hh binding to Ptc alters the composition and localization of this and derivative protein complexes in ways that are sensitive to Hh concentration (reviewed in Hooper and Scott 2005; Ogden et al. …

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