Hypomorphic Smo mutant with inefficient ciliary enrichment disrupts the highest level of vertebrate Hedgehog response

• Type of Material: Article
• Authors: Eduardo D. Gigante, Emory University; Alyssa Bushey Long, Emory University; Johanna Ben-Ami, Emory University; Tamara Caspary, Emory University
• Language: English
• Date: 2018-05-15
• Publisher: Elsevier
• Publication Version: Author Accepted Manuscript (After Peer Review)
• Copyright Statement: © 2018 Elsevier Inc.
• License: Creative Commons Attribution-NonCommercial-NoDerivs 4.0 International
• Final Published Version (URL): http://dx.doi.org/10.1016/j.ydbio.2018.03.019
• Title of Journal or Parent Work: Developmental Biology
• ISSN: 0012-1606
• Volume: 437
• Issue: 2
• Start Page: 152
• End Page: 162
• Grant/Funding Information: Further support came from the Emory University Integrated Cellular Imaging Microscopy Core of the Emory Neuroscience NINDS Core Facilities grant, P30NS055077, as well as the Mouse Mutant Re-sequencing Project at the Broad Institute funded by NHGRI under grant U54 HG003067.; E.D.G was supported by NIH training grant T32NS096050.; This work was supported by funding from NIH grants R01GM110663, R01NS090029, and R35GM122549 to T.C.
• Keywords: Sonic hedgehog signaling; PRIMITIVE NEUROECTODERMAL TUMORS; VENTRAL NEURAL-TUBE; POLARIZING ACTIVITY; Science & Technology; CENTRAL-NERVOUS-SYSTEM; PRIMARY CILIUM; Life Sciences & Biomedicine; Smoothened; SIGNAL-TRANSDUCTION; Developmental Biology; FLOOR PLATE; SMOOTHENED ACTIVITY; SONIC-HEDGEHOG; INTRAFLAGELLAR TRANSPORT; Primary cilia; Mouse development
• Research Categories: Biology, Genetics; Biology, Neuroscience

Abstract

Smoothened (Smo) is the essential transducer of Sonic hedgehog (Shh) signaling, which regulates cell fate and proliferation during embryogenesis. We identified a novel mouse mutant, cabbie (cbb), and found that its cause is a missense mutation in Smo. We showed the Smocbb mutation is insensitive to the Shh agonist SAG, perhaps due to the disruption of SAG binding. We characterized Smocbb for defects in craniofacial and skeletal development, as well as neural tube patterning, and revealed Smocbb affected processes that require the highest levels of Shh activity. Smo is normally enriched in cilia upon Shh stimulation; however, we detected inefficient enrichment of Smo in Smocbb mutants whether we stimulated with Shh or SAG. Taken together, our data suggest that the highest levels of vertebrate Hedgehog signaling activity require efficient Smo ciliary enrichment.