Ankmy2 Prevents Smoothened-Independent Hyperactivation of the Hedgehog Pathway via Cilia-Regulated Adenylyl Cyclase Signaling

Bandarigoda Nipunika Somatilaka, Sun Hee Hwang, Vivek Reddy Palicharla, Kevin Andrew White, Hemant Badgandi, John Michael Shelton, Saikat Mukhopadhyay

Research output: Contribution to journalArticlepeer-review

2 Scopus citations

Abstract

The mechanisms underlying subcellular targeting of cAMP-generating adenylyl cyclases and processes regulated by their compartmentalization are poorly understood. Here, we identify Ankmy2 as a repressor of the Hedgehog pathway via adenylyl cyclase targeting. Ankmy2 binds to multiple adenylyl cyclases, determining their maturation and trafficking to primary cilia. Mice lacking Ankmy2 are mid-embryonic lethal. Knockout embryos have increased Hedgehog signaling and completely open neural tubes showing co-expansion of all ventral neuroprogenitor markers, comparable to the loss of the Hedgehog receptor Patched1. Ventralization in Ankmy2 knockout is completely independent of the Hedgehog pathway transducer Smoothened. Instead, ventralization results from the reduced formation of Gli2 and Gli3 repressors and early depletion of adenylyl cyclase III in neuroepithelial cilia, implicating deficient pathway repression. Ventralization in Ankmy2 knockout requires both cilia and Gli2 activation. These findings indicate that cilia-dependent adenylyl cyclase signaling represses the Hedgehog pathway and promotes morphogenetic patterning.

Original languageEnglish (US)
Pages (from-to)710-726.e8
JournalDevelopmental cell
Volume54
Issue number6
DOIs
StatePublished - Sep 28 2020

Keywords

  • ACIII
  • Ankmy2
  • Gli repressor
  • Smoothened
  • adenylyl cyclase
  • cAMP
  • neural tube
  • primary cilia
  • protein kinase A
  • sonic hedgehog

ASJC Scopus subject areas

  • Molecular Biology
  • Biochemistry, Genetics and Molecular Biology(all)
  • Developmental Biology
  • Cell Biology

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