title: The endocytic recycling regulatory protein EHD1 Is required for ocular lens development.
abstract: The C-terminal Eps15 homology domain-containing (EHD) proteins play a key role in endocytic recycling, a fundamental cellular process that ensures the return of endocytosed membrane components and receptors back to the cell surface. To define the in vivo biological functions of EHD1, we have generated Ehd1 knockout mice and previously reported a requirement of EHD1 for spermatogenesis. Here, we show that approximately 56% of the Ehd1-null mice displayed gross ocular abnormalities, including anophthalmia, aphakia, microphthalmia and congenital cataracts. Histological characterization of ocular abnormalities showed pleiotropic defects that include a smaller or absent lens, persistence of lens stalk and hyaloid vasculature, and deformed optic cups. To test whether these profound ocular defects resulted from the loss of EHD1 in the lens or in non-lenticular tissues, we deleted the Ehd1 gene selectively in the presumptive lens ectoderm using Le-Cre. Conditional Ehd1 deletion in the lens resulted in developmental defects that included thin epithelial layers, small lenses and absence of corneal endothelium. Ehd1 deletion in the lens also resulted in reduced lens epithelial proliferation, survival and expression of junctional proteins E-cadherin and ZO-1. Finally, Le-Cre-mediated deletion of Ehd1 in the lens led to defects in corneal endothelial differentiation. Taken together, these data reveal a unique role for EHD1 in early lens development and suggest a previously unknown link between the endocytic recycling pathway and regulation of key developmental processes including proliferation, differentiation and morphogenesis.
authors.affiliation: Department of Genetics, Cell Biology & Anatomy, College of Medicine, University of Nebraska Medical Center, 985805 Nebraska Medical Center Omaha, NE 68198-5805, USA; Eppley Institute for Research in Cancer and Allied Diseases, University of Nebraska Medical Center, 985950 Nebraska Medical Center, NE 68198-5950, USA. Electronic address: priyanka.arya@unmc.edu.
authors.forename: Priyanka
authors.initials: P
authors.lastname: Arya
authors.affiliation: Eppley Institute for Research in Cancer and Allied Diseases, University of Nebraska Medical Center, 985950 Nebraska Medical Center, NE 68198-5950, USA. Electronic address: markrainey@gmail.com.
authors.forename: Mark A
authors.initials: MA
authors.lastname: Rainey
authors.affiliation: Eppley Institute for Research in Cancer and Allied Diseases, University of Nebraska Medical Center, 985950 Nebraska Medical Center, NE 68198-5950, USA; Department of Pathology & Microbiology, College of Medicine, University of Nebraska Medical Center, 985900 Nebraska Medical Center Omaha, NE 68198-5900, USA. Electronic address: sbhatta@unmc.edu.
authors.forename: Sohinee
authors.initials: S
authors.lastname: Bhattacharyya
authors.affiliation: Eppley Institute for Research in Cancer and Allied Diseases, University of Nebraska Medical Center, 985950 Nebraska Medical Center, NE 68198-5950, USA; Department of Biochemistry & Molecular Biology, College of Medicine, University of Nebraska Medical Center, 985870 Nebraska Medical Center Omaha, NE 68198-5870, USA. Electronic address: bmohapat@unmc.edu.
authors.forename: Bhopal C
authors.initials: BC
authors.lastname: Mohapatra
authors.affiliation: Eppley Institute for Research in Cancer and Allied Diseases, University of Nebraska Medical Center, 985950 Nebraska Medical Center, NE 68198-5950, USA. Electronic address: mgeorge@unmc.edu.
authors.forename: Manju
authors.initials: M
authors.lastname: George
authors.affiliation: Department of Biomedical Sciences, Creighton University, 2500 California Plaza, Omaha, NE 68178, USA. Electronic address: muralikuracha@creighton.edu.
authors.forename: Murali R
authors.initials: MR
authors.lastname: Kuracha
authors.affiliation: Eppley Institute for Research in Cancer and Allied Diseases, University of Nebraska Medical Center, 985950 Nebraska Medical Center, NE 68198-5950, USA. Electronic address: mstorck@unmc.edu.
authors.forename: Matthew D
authors.initials: MD
authors.lastname: Storck
authors.affiliation: Department of Genetics, Cell Biology & Anatomy, College of Medicine, University of Nebraska Medical Center, 985805 Nebraska Medical Center Omaha, NE 68198-5805, USA; Eppley Institute for Research in Cancer and Allied Diseases, University of Nebraska Medical Center, 985950 Nebraska Medical Center, NE 68198-5950, USA; Fred & Pamela Buffett Cancer Center, University of Nebraska Medical Center, 985950 Nebraska Medical Center Omaha, NE 68198-5950, USA. Electronic address: vband@unmc.edu.
authors.forename: Vimla
authors.initials: V
authors.lastname: Band
authors.affiliation: Department of Biomedical Sciences, Creighton University, 2500 California Plaza, Omaha, NE 68178, USA. Electronic address: g.v@creighton.edu.
authors.forename: Venkatesh
authors.initials: V
authors.lastname: Govindarajan
authors.affiliation: Department of Genetics, Cell Biology & Anatomy, College of Medicine, University of Nebraska Medical Center, 985805 Nebraska Medical Center Omaha, NE 68198-5805, USA; Eppley Institute for Research in Cancer and Allied Diseases, University of Nebraska Medical Center, 985950 Nebraska Medical Center, NE 68198-5950, USA; Department of Pathology & Microbiology, College of Medicine, University of Nebraska Medical Center, 985900 Nebraska Medical Center Omaha, NE 68198-5900, USA; Department of Biochemistry & Molecular Biology, College of Medicine, University of Nebraska Medical Center, 985870 Nebraska Medical Center Omaha, NE 68198-5870, USA; Fred & Pamela Buffett Cancer Center, University of Nebraska Medical Center, 985950 Nebraska Medical Center Omaha, NE 68198-5950, USA. Electronic address: hband@unmc.edu.
authors.forename: Hamid
authors.initials: H
authors.lastname: Band
mesh_terms: D000818:Animals; D002386:Cataract / Q000150:complications / Q000196:embryology / Q000235:genetics / Q000473:pathology; D002454:Cell Differentiation; D016764:Cell Polarity; D002470:Cell Survival; D004622:Embryo, Mammalian / Q000473:pathology; D004705:Endocytosis; D004728:Endothelium, Corneal / Q000378:metabolism / Q000473:pathology; D004847:Epithelial Cells / Q000473:pathology; D005124:Eye Abnormalities / Q000235:genetics / Q000473:pathology; D017353:Gene Deletion; D018507:Gene Expression Regulation, Developmental; D007908:Lens, Crystalline / Q000196:embryology* / Q000378:metabolism* / Q000473:pathology; D018345:Mice, Knockout; D008850:Microphthalmos / Q000150:complications / Q000196:embryology / Q000235:genetics; D010641:Phenotype; D033921:Vesicular Transport Proteins / Q000172:deficiency / Q000378:metabolism*
chemical_list: C485640:Ehd1 protein, mouse; D033921:Vesicular Transport Proteins
keywords: Apoptosis; Corneal endothelium; EHD1; Endocytic recycling; Lens development; Lens epithelium; Polarity; Proliferation