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Molecular and Cellular Biology, September 2008, p. 5209-5222, Vol. 28, No. 17
0270-7306/08/$08.00+0     doi:10.1128/MCB.00360-08
Copyright © 2008, American Society for Microbiology. All Rights Reserved.

Hair Loss and Defective T- and B-Cell Function in Mice Lacking ORAI1{triangledown} ,{dagger}

Yousang Gwack ,1,¶,# Sonal Srikanth,1,¶,# Masatsugu Oh-hora,1,¶ Patrick G. Hogan,1 Edward D. Lamperti,1 Megumi Yamashita,2 Curtis Gelinas,1 Daniel S. Neems,1 Yoshiteru Sasaki,1,§ Stefan Feske,1,{ddagger} Murali Prakriya,2 Klaus Rajewsky,1 and Anjana Rao*

Department of Pathology, Harvard Medical School and Immune Disease Institute, 200 Longwood Avenue, Boston, Massachusetts 02115,1 Department of Molecular Pharmacology and Biological Chemistry, Northwestern University, Feinberg School of Medicine, Chicago, Illinois 606112

Received 3 March 2008/ Returned for modification 29 April 2008/ Accepted 23 June 2008

ORAI1 is a pore subunit of the store-operated Ca2+ release-activated Ca2+ (CRAC) channel. To examine the physiological consequences of ORAI1 deficiency, we generated mice with targeted disruption of the Orai1 gene. The results of immunohistochemical analysis showed that ORAI1 is expressed in lymphocytes, skin, and muscle of wild-type mice and is not expressed in Orai1–/– mice. Orai1–/– mice with the inbred C57BL/6 background showed perinatal lethality, which was overcome by crossing them to outbred ICR mice. Orai1–/– mice were small in size, with eyelid irritation and sporadic hair loss resembling the cyclical alopecia observed in mice with keratinocyte-specific deletion of the Cnb1 gene. T and B cells developed normally in Orai1–/– mice, but B cells showed a substantial decrease in Ca2+ influx and cell proliferation in response to B-cell receptor stimulation. Naïve and differentiated Orai1–/– T cells showed substantial reductions in store-operated Ca2+ entry, CRAC currents, and cytokine production. These features are consistent with the severe combined immunodeficiency and mild extraimmunological symptoms observed in a patient with a missense mutation in human ORAI1 and distinguish the ORAI1-null mice described here from a previously reported Orai1 gene-trap mutant mouse which may be a hypomorph rather than a true null.

* Corresponding author. Mailing address: Department of Pathology, Harvard Medical School and the Immune Disease Institute, Rm. 152, Warren Alpert Bldg., Harvard Medical School, 200 Longwood Avenue, Boston, MA 02115. Phone: (617) 278-3261. Fax: (617) 278-3280. E-mail: arao{at}idi.harvard.edu

{triangledown} Published ahead of print on 30 June 2008.

{dagger} Supplemental material for this article may be found at http://mcb.asm.org/.

# Present address: Department of Physiology, David Geffen School of Medicine at UCLA, 53-266 Center for Health Sciences, 10833 Le Conte Avenue, Los Angeles, CA 90095-1751.

Y. Gwack, S. Srikanth, and M. Oh-hora made equal contributions.

§ Present address: Laboratory for Stem Cell Biology, Riken Center for Developmental Biology, Kobe, Hyogo 650-0047, Japan.

{ddagger} Present address: Department of Pathology, New York University, School of Medicine, New York, NY 10016.

Molecular and Cellular Biology, September 2008, p. 5209-5222, Vol. 28, No. 17
0270-7306/08/$08.00+0     doi:10.1128/MCB.00360-08
Copyright © 2008, American Society for Microbiology. All Rights Reserved.



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