@article{2bf6b104a92b4353ad9fc854d93a88be,
title = "Endocytic recycling protein EHD1 regulates primary cilia morphogenesis and SHH signaling during neural tube development",
abstract = "Members of the four-member C-terminal EPS15-Homology Domain-containing (EHD) protein family play crucial roles in endocytic recycling of cell surface receptors from endosomes to the plasma membrane. In this study, we show that Ehd1 gene knockout in mice on a predominantly B6 background is embryonic lethal. Ehd1-null embryos die at mid-gestation with a failure to complete key developmental processes including neural tube closure, axial turning and patterning of the neural tube. We found that Ehd1-null embryos display short and stubby cilia on the developing neuroepithelium at embryonic day 9.5 (E9.5). Loss of EHD1 also deregulates the ciliary SHH signaling with Ehd1-null embryos displaying features indicative of increased SHH signaling, including a significant downregulation in the formation of the GLI3 repressor and increase in the ventral neuronal markers specified by SHH. Using Ehd1-null MEFS we found that EHD1 protein co-localizes with the SHH receptor Smoothened in the primary cilia upon ligand stimulation. Under the same conditions, EHD1 was shown to co-traffic with Smoothened into the developing primary cilia and we identify EHD1 as a direct binding partner of Smoothened. Overall, our studies identify the endocytic recycling regulator EHD1 as a novel regulator of the primary cilium-associated trafficking of Smoothened and Hedgehog signaling.",
author = "Sohinee Bhattacharyya and Rainey, {Mark A.} and Priyanka Arya and Samikshan Dutta and Manju George and Storck, {Matthew D.} and McComb, {Rodney D.} and David Muirhead and Todd, {Gordon L.} and Karen Gould and Kaustubh Datta and Waes, {Janee Gelineau Van} and Vimla Band and Hamid Band",
note = "Funding Information: We thank Dr. Jonathan Eggenschwiler (Columbia University) for his generous gift of the Gli2 antibody. We thank Dr. Kathryn Anderson (Memorial Sloan-Kettering Cancer Center) and Dr. Raj Rohatgi (Stanford University) for their generous gift of the Anti-Smoothened antibody. We thank James Talaska and Janice Taylor for helping with confocal microscopy. We thank Melissa Holzapfel and Tom Bargar for their help with TEM and SEM respectively. We thank members of the Tissue Science facilities at UNMC for their technical support. We thank members of the Band Laboratory for discussion and suggestions.S.B. and P.A. were recipients of graduate fellowships through the Program of Excellence Graduate Assistantships from UNMC. This work was supported by the NIH grants CA105489, CA87986, CA99163 and CA116552 to H.B., CA96844 and CA144027 to V.B., and CA140432, CA182435A to SD and KD Nebraska Department of Health and Human Services LB506 (2014-01) and LB606 (18123-Y3) grants to H.B.; Department of Defense grants W81XWH-07-1-0351 and W81XWH-11-1-0171 to V.B.; the NCI/NIH CCSG to Buffett Cancer Center; and the NIGMS/NIH P30 GM106397 Institutional Development Award (IDeA).",
year = "2016",
month = feb,
day = "17",
doi = "10.1038/srep20727",
language = "English (US)",
volume = "6",
journal = "Scientific reports",
issn = "2045-2322",
publisher = "Nature Research",
}