The ciliary phosphatidylinositol phosphatase Inpp5e plays positive and negative regulatory roles in Shh signaling

• Type of Material: Article
• Authors: Sandii Constable, Emory University; Alyssa B. Long, Emory University; Katharine A. Floyd, Emory University; Stéphane Schurmans, University of Liege; Tamara Caspary, Emory University
• Language: English
• Date: 2020-02-01
• Publisher: Company Biologists Ltd.
• Publication Version: Final Published Version
• Copyright Statement: © 2020. Published by The Company of Biologists Ltd.
• Final Published Version (URL): http://dx.doi.org/10.1242/dev.183301
• Title of Journal or Parent Work: Development
• Volume: 147
• Issue: 3
• Grant/Funding Information: We also had additional support from the Emory University Integrated Cellular Imaging Microscopy Core of the Emory Neuroscience NINDS (Core Facilities grant P30NS055077).; This work was supported by funding from National Institutes of Health (R01NS090029, R01GM110663 and R35GM122549) as well as by a March of Dimes Foundation grant (FY15-343).
• Keywords: Neural tube patterning; Developmental Biology; Morphogen gradient; Primary cilium; Life Sciences & Biomedicine; Floor plate; Defects; Science & Technology; Progenitor cell identity; Mouse; Sonic hedgehog; Phosphatidylinositol phosphatase; Inpp5e; Trafficking; Neuronal; Cilia; Mutations
• Research Categories: Biology, Genetics; Biology, Cell; Health Sciences, Human Development

Abstract

Sonic hedgehog (Shh) signal transduction specifies ventral cell fates in the neural tube and is mediated by the Gli transcription factors that play both activator (GliA) and repressor (GliR) roles. Cilia are essential for Shh signal transduction and the ciliary phosphatidylinositol phosphatase Inpp5e is linked to Shh regulation. In the course of a forward genetic screen for recessive mouse mutants, we identified a functional null allele of inositol polyphosphate-5-phosphatase E (Inpp5e), ridge top (rdg), with expanded ventral neural cell fates at E10.5. By E12.5, Inpp5erdg/rdg embryos displayed normal neural patterning and this correction over time required Gli3, the predominant repressor in neural patterning. Inpp5erdg function largely depended on the presence of cilia and on smoothened, the obligate transducer of Shh signaling, indicating that Inpp5e functions within the cilium to regulate the pathway. These data indicate that Inpp5e plays a more complicated role in Shh signaling than previously appreciated. We propose that Inpp5e attenuates Shh signaling in the neural tube through regulation of the relative timing of GliA and GliR production, which is important in understanding how the duration of Shh signaling regulates neural tube patterning.