title: Male infertility in mice lacking the store-operated Ca(2+) channel Orai1.
abstract: Store-operated calcium entry (SOCE) is an important Ca(2+) influx pathway in somatic cells. In addition to maintaining endoplasmic reticulum (ER) Ca(2+) stores, Ca(2+) entry through store-operated channels regulates essential signaling pathways in numerous cell types. Patients with mutations in the store-operated channel subunit ORAI1 exhibit defects in store-operated Ca(2+) influx, along with severe immunodeficiency, congenital myopathy and ectodermal dysplasia. However, little is known about the functional role of ORAI1 in germ cells and reproductive function in mice, or in men, since men with loss-of-function or null mutations in ORAI1 rarely survive to reproductive age. In this study, we investigated the role of ORAI1 in male reproductive function. We reveal that Orai1(-/-) male mice are sterile and have severe defects in spermatogenesis, with prominent deficiencies in mid- to late-stage elongating spermatid development. These studies establish an essential in vivo role for store-operated ORAI1 channels in male reproductive function and identify these channels as potential non-steroidal regulators of male fertility.
authors.affiliation: Signal Transduction Laboratory, National Institute of Environmental Health Sciences, National Institutes of Health, Research Triangle Park, NC 27709, USA.
authors.forename: Felicity M
authors.initials: FM
authors.lastname: Davis
authors.affiliation: Reproductive and Developmental Biology Laboratory, National Institute of Environmental Health Sciences, National Institutes of Health, Research Triangle Park, NC 27709, USA.
authors.forename: Eugenia H
authors.initials: EH
authors.lastname: Goulding
authors.affiliation: Signal Transduction Laboratory, National Institute of Environmental Health Sciences, National Institutes of Health, Research Triangle Park, NC 27709, USA.
authors.forename: Diane M
authors.initials: DM
authors.lastname: D'Agostin
authors.affiliation: Integrated Laboratory Systems, Inc., Research Triangle Park, NC 27709, USA.
authors.forename: Kyathanahalli S
authors.initials: KS
authors.lastname: Janardhan
authors.affiliation: UltraPath Imaging, Research Triangle Park, NC 27709, USA.
authors.forename: Connie A
authors.initials: CA
authors.lastname: Cummings
authors.affiliation: Signal Transduction Laboratory, National Institute of Environmental Health Sciences, National Institutes of Health, Research Triangle Park, NC 27709, USA.
authors.forename: Gary S
authors.initials: GS
authors.lastname: Bird
authors.affiliation: Reproductive and Developmental Biology Laboratory, National Institute of Environmental Health Sciences, National Institutes of Health, Research Triangle Park, NC 27709, USA.
authors.forename: Edward M
authors.initials: EM
authors.lastname: Eddy
authors.affiliation: Signal Transduction Laboratory, National Institute of Environmental Health Sciences, National Institutes of Health, Research Triangle Park, NC 27709, USA. Electronic address: putney@niehs.nih.gov.
authors.forename: James W
authors.initials: JW
authors.lastname: Putney
mesh_terms: D000818:Animals; D002118:Calcium / Q000378:metabolism*; D020013:Calcium Signaling / Q000502:physiology*; D002469:Cell Separation / Q000379:methods; D004721:Endoplasmic Reticulum / Q000378:metabolism*; D005260:Female; D007248:Infertility, Male / Q000378:metabolism*; D008297:Male; D051379:Mice; D000071740:ORAI1 Protein / Q000172:deficiency / Q000378:metabolism*
chemical_list: D000071740:ORAI1 Protein; C520430:Orai1 protein, mouse; D002118:Calcium
keywords: Ca(2+); Fertility; Orai1; Reproduction; Spermatogenesis; Store-operated calcium entry (SOCE)