The imprinted gene Magel2 regulates normal circadian output.
Mammalian circadian rhythms of activity are generated within the suprachiasmatic nucleus (SCN). Transcripts from the imprinted, paternally expressed Magel2 gene, which maps to the chromosomal region associated with Prader-Willi Syndrome (PWS), are highly enriched in the SCN. The Magel2 message is circadianly expressed and peaks during the subjective day. Mice deficient in Magel2 expression entrain to light cycles and express normal running-wheel rhythms, but with markedly reduced amplitude of activity and increased daytime activity. These changes are associated with reductions in food intake and male fertility. Orexin levels and orexin-positive neurons in the lateral hypothalamus are substantially reduced, suggesting that some of the consequences of Magel2 loss are mediated through changes in orexin signaling. The robust rhythmicity of Magel2 expression in the SCN and the altered behavioral rhythmicity of null mice reveal Magel2 to be a clock-controlled circadian output gene whose disruption results in some of the phenotypes characteristic of PWS.
Kozlov
Serguei V
SV
Cancer and Developmental Biology Laboratory, National Cancer Institute, Frederick, Maryland 21702, USA.
Bogenpohl
James W
JW
Howell
Maureen P
MP
Wevrick
Rachel
R
Panda
Satchin
S
Hogenesch
John B
JB
Muglia
Louis J
LJ
Van Gelder
Russell N
RN
Herzog
Erik D
ED
Stewart
Colin L
CL
D000818:Animals; D000951:Antigens, Neoplasm / Q000235:genetics* / Q000378:metabolism; D002940:Circadian Rhythm / Q000235:genetics*; D005260:Female; D005786:Gene Expression Regulation; D018392:Genomic Imprinting; D007150:Immunohistochemistry; D047908:Intracellular Signaling Peptides and Proteins / Q000378:metabolism; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D009479:Neuropeptides / Q000378:metabolism; D000068797:Orexins; D010641:Phenotype; D011218:Prader-Willi Syndrome / Q000235:genetics / Q000378:metabolism; D011506:Proteins / Q000235:genetics* / Q000378:metabolism; D013493:Suprachiasmatic Nucleus / Q000196:embryology / Q000378:metabolism; D064267:Intrinsically Disordered Proteins
D000951:Antigens, Neoplasm; D047908:Intracellular Signaling Peptides and Proteins; D009479:Neuropeptides; D000068797:Orexins; D011506:Proteins; C403091:Magel2 protein, mouse; D064267:Intrinsically Disordered Proteins