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Isoform-Specific Expression of Hypoxia-Inducible Factor-1 During the Late Stages of Mouse Spermiogenesis

Max-Planck-Institute for Physiological and Clinical Research (H.H.M.), Department of Molecular Cell Biology, D-61231 Bad Nauheim, Germany; Institute of Physiology (D.M.K., K.F.W., B.S., R.H.W.) and Clinic of Anaesthesiology (K.F.W.), Medical University of Lübeck, D-23538 Lübeck, Germany; and Department of Obstetrics and Gynaecology (L.S.), University Hospital Zürich, CH-8091 Zürich, Switzerland

Address all correspondence and requests for reprints to: Roland H. Wenger, Ph.D., Carl-Ludwig-Institut für Physiologie, Universität Leipzig, Liebigstrasse 27, D-04103 Leipzig, Germany. E-mail: wenr{at}medizin.uni-leipzig.de

The heterodimeric hypoxia-inducible factor (HIF)-1 is a transcriptional master regulator of several genes involved in mammalian oxygen homeostasis, including erythropoietin, vascular endothelial growth factor, and factors involved in glucose transport and metabolism. The mouse Hif1a gene is expressed from two distinct promoter/first exon combinations resulting in tissue-specific (mHIF-1I.1) and ubiquitous (mHIF-1I.2) mRNA isoforms. By in situ hybridization, we detected mHIF-1I.1 mRNA exclusively in the elongated spermatids of the testis. In vitro studies indicated that the switch from mHIF-1I.2 to mHIF-1I.1 mRNA expression does not occur at the premeiotic stages of mouse spermatogenesis. Exposure of mice to hypoxic conditions induced mHIF-1I.2 protein in spermatocytes and probably in Sertoli cells but not in spermatogonia. In contrast, expression of the putative mHIF-1I.1 protein in spermatozoa of the testis and epididymis was oxygen independent and located to the midpiece of the spermatozoal flagellum. Both the switch in transcript expression during spermiogenesis and the unexpected protein localization in mature sperm cells suggest a so far unrecognized function of HIF-1.

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