Huntingtin interacting protein 1 is a clathrin coat binding protein required for differentiation of late spermatogenic progenitors

Huntingtin-interacting protein 1 (HIP1) interacts with huntingtin, the prot ein whose gene is mutated in Huntington's disease. In addition, a fusion be tween 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-termi nal homology, domain, which is found in proteins involved in clathrin-media ted endocytosis. HIP1 and HIP1r also share a central leucine zipper and an actin binding TALIN homology domain. Here we show that HIP1, like HIP1r, co localizes with clathrin coat components. We also show that HIP1 physically associates with clathrin and AP-2, the major components of the clathrin coa t. To further understand the putative biological role(s) of HIP1, we have g enerated a targeted deletion of murine HIP1. HIP1(-/-) mice developed into adulthood, did not develop overt neurologic symptoms in the first year of l ife, and had normal peripheral blood counts. However, HIP1-deficient mice e xhibited testicular degeneration with increased apoptosis of postmeiotic sp ermatids. Postmeiotic spermatids are the only cells of the seminiferous tub ules that express HIP1. These findings indicate that HIP1 is required for d ifferentiation, proliferation, and/or survival of spermatogenic progenitors . The association of HIP1 with clathrin coats and the requirement of HIP1 f or progenitor survival suggest a role for HIP1 in the regulation of endocyt osis.