Hair loss and defective T- and B-cell function in mice lacking ORAI1.
ORAI1 is a pore subunit of the store-operated Ca(2+) release-activated Ca(2+) (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 Ca(2+) influx and cell proliferation in response to B-cell receptor stimulation. Naïve and differentiated Orai1(-/-) T cells showed substantial reductions in store-operated Ca(2+) 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.
Gwack
Yousang
Y
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, USA.
Srikanth
Sonal
S
Oh-Hora
Masatsugu
M
Hogan
Patrick G
PG
Lamperti
Edward D
ED
Yamashita
Megumi
M
Gelinas
Curtis
C
Neems
Daniel S
DS
Sasaki
Yoshiteru
Y
Feske
Stefan
S
Prakriya
Murali
M
Rajewsky
Klaus
K
Rao
Anjana
A
D000818:Animals; D001402:B-Lymphocytes / Q000276:immunology / Q000378:metabolism / Q000473:pathology*; D015220:Calcium Channels / Q000172:deficiency* / Q000378:metabolism; D020013:Calcium Signaling; D002454:Cell Differentiation; D049109:Cell Proliferation; D016207:Cytokines / Q000096:biosynthesis; D004817:Epidermis / Q000473:pathology; D005347:Fibroblasts / Q000166:cytology / Q000378:metabolism; D006197:Hair / Q000276:immunology / Q000473:pathology*; D015640:Ion Channel Gating; D016131:Lymphocyte Subsets / Q000473:pathology; D051379:Mice; D008810:Mice, Inbred C57BL; D008813:Mice, Inbred ICR; D018345:Mice, Knockout; D000071740:ORAI1 Protein; D000071741:ORAI2 Protein; D010641:Phenotype; D013601:T-Lymphocytes / Q000276:immunology / Q000378:metabolism / Q000473:pathology*
D015220:Calcium Channels; D016207:Cytokines; D000071740:ORAI1 Protein; D000071741:ORAI2 Protein; C520430:Orai1 protein, mouse; C520431:Orai2 protein, mouse