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Molecular and Cellular Biology, November 2001, p. 7796-7806, Vol. 21, No. 22
0270-7306/01/$04.00+0   DOI: 10.1128/MCB.21.22.7796-7806.2001
Copyright © 2001, American Society for Microbiology. All rights reserved.

Huntingtin Interacting Protein 1 Is a Clathrin Coat Binding Protein Required for Differentiation of late Spermatogenic Progenitors

Dinesh S. Rao,1 Jenny C. Chang,1 Priti D. Kumar,1 Ikuko Mizukami,1 Glennda M. Smithson,1,dagger Sarah V. Bradley,1 A. F. Parlow,2 and Theodora S. Ross1,*

Division of Hematology and Oncology, Department of Internal Medicine, University of Michigan Medical School, Ann Arbor, Michigan 48109-0936,1 and National Hormone and Peptide Program, Harbor-UCLA Medical Center, Torrance, California 905092

Received 30 May 2001/Returned for modification 14 June 2001/Accepted 6 August 2001

Huntingtin-interacting protein 1 (HIP1) interacts with huntingtin, the protein whose gene is mutated in Huntington's disease. In addition, a fusion between HIP1 and platelet-derived growth factor beta  receptor causes chronic myelomonocytic leukemia. The HIP1 proteins, including HIP1 and HIP1-related (HIP1r), have an N-terminal polyphosphoinositide-interacting epsin N-terminal homology, domain, which is found in proteins involved in clathrin-mediated endocytosis. HIP1 and HIP1r also share a central leucine zipper and an actin binding TALIN homology domain. Here we show that HIP1, like HIP1r, colocalizes with clathrin coat components. We also show that HIP1 physically associates with clathrin and AP-2, the major components of the clathrin coat. To further understand the putative biological role(s) of HIP1, we have generated a targeted deletion of murine HIP1. HIP1-/- mice developed into adulthood, did not develop overt neurologic symptoms in the first year of life, and had normal peripheral blood counts. However, HIP1-deficient mice exhibited testicular degeneration with increased apoptosis of postmeiotic spermatids. Postmeiotic spermatids are the only cells of the seminiferous tubules that express HIP1. These findings indicate that HIP1 is required for differentiation, proliferation, and/or survival of spermatogenic progenitors. The association of HIP1 with clathrin coats and the requirement of HIP1 for progenitor survival suggest a role for HIP1 in the regulation of endocytosis.

* Corresponding author. Mailing address: Division of Hematology and Oncology, Department of Internal Medicine, University of Michigan Medical School, Ann Arbor, MI 48109-0936. Phone: (734) 615-5509. Fax: (734) 647-9654. E-mail: tsross{at}umich.edu.

dagger Present address: Curagen Corp., Bradford, CT 06405.

Molecular and Cellular Biology, November 2001, p. 7796-7806, Vol. 21, No. 22
0270-7306/01/$04.00+0   DOI: 10.1128/MCB.21.22.7796-7806.2001
Copyright © 2001, American Society for Microbiology. All rights reserved.


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