Drosophila hedgehog can act as a morphogen in the absence of regulated Ci processing.

Jamie C Little,Amanda Sul,Daniel Kalderon,Elisa Garcia-Garcia

doi:10.7554/elife.61083

Abstract

Extracellular Hedgehog (Hh) proteins induce transcriptional changes in target cells by inhibiting the proteolytic processing of full-length Drosophila Ci or mammalian Gli proteins to nuclear transcriptional repressors and by activating the full-length Ci or Gli proteins. We used Ci variants expressed at physiological levels to investigate the contributions of these mechanisms to dose-dependent Hh signaling in Drosophila wing imaginal discs. Ci variants that cannot be processed supported a normal pattern of graded target gene activation and the development of adults with normal wing morphology, when supplemented by constitutive Ci repressor, showing that Hh can signal normally in the absence of regulated processing. The processing-resistant Ci variants were also significantly activated in the absence of Hh by elimination of Cos2, likely acting through binding the CORD domain of Ci, or PKA, revealing separate inhibitory roles of these two components in addition to their well-established roles in promoting Ci processing.

Highlights

Hedgehog (Hh) signaling proteins guide development and help maintain adult tissue homeostasis in both invertebrates and vertebrates (Hui and Angers, 2011; Ingham and McMahon, 2001; Petrova and Joyner, 2014)
We used Cubitus Interruptus (Ci) variants expressed at physiological levels to investigate the contributions of these mechanisms to dose-dependent Hh signaling at the anteroposterior (AP) border of Drosophila wing imaginal discs
Ci variants that cannot be processed supported a normal pattern of graded target gene activation and the development of adults with normal wing morphology when supplemented by constitutive Ci repressor, showing that Hh can signal normally in the absence of regulated processing

Summary

Introduction

Hedgehog (Hh) signaling proteins guide development and help maintain adult tissue homeostasis in both invertebrates and vertebrates (Hui and Angers, 2011; Ingham and McMahon, 2001; Petrova and Joyner, 2014). Aberrant Hh protein production, distribution, and responses are common causes of developmental birth defects and cancer including holoprosencephaly, limb and digit abnormalities, medulloblastoma and basal cell carcinoma (Anderson et al, 2012; Cortes et al, 2019; Ng and Curran, 2011; Pak and Segal, 2016; Petrova and Joyner, 2014; Sasai et al, 2019). Many conserved Hh components were initially identified in Drosophila melanogaster and found to have a mammalian ortholog, including the key transducing protein Smoothened (Smo), which is the target of several anti-cancer drugs (Cortes et al, 2019; Ng and Curran, 2011; Pak and Segal, 2016). It is important to understand the precise molecular mechanisms involved in the pathway in Drosophila, which allows complex genetic tests under physiological conditions

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