Germline Deletion of Huntingtin Causes Male Infertility and Arrested Spermiogenesis in Mice

Abstract

Human Huntingtin (HTT), a Huntington's disease gene, is highly expressed in the mammalian brain and testis. Simultaneous knockout of mouse Huntingtin (Htt) in brain and testis impairs male fertility, providing evidence for a link between Htt and spermatogenesis; however, the underlying mechanism remains unclear. To understand better the function of Htt in spermatogenesis, we restricted recombination specifically to the germ cells using the Cre/loxP site-specific recombination strategy and found that the mice manifest smaller testes, azoospermia, and complete male infertility. The meiotic chromosome spread experiments showed that the process of meiosis is normal in the absence of Htt. Notably, we found that Htt-deficient round spermatids did not progress beyond step 3 during post-meiotic phase when round spermatids differentiate into mature spermatozoa. Using iTRAQ-based quantitative proteomic assay, we found that knockout of Htt significantly altered the testis protein profile. The differentially expressed proteins exhibited a remarkable enrichment for proteins involved in translation regulation and DNA packaging, suggesting that Htt may play a role in spermatogenesis by regulating translation and DNA packaging in the testis.