title: Aberrant development of the suprachiasmatic nucleus and circadian rhythms in mice lacking the homeodomain protein Six6.
abstract: The suprachiasmatic nucleus (SCN) of the mammalian hypothalamus is the central pacemaker for peripheral and organismal circadian rhythms. The development of this hypothalamic structure depends on genetic programs throughout embryogenesis. We have investigated the role of the homeodomain transcription factor Six6 in the development of the SCN. We first showed that Six6 mRNA has circadian regulation in the mouse SCN. We then characterized the behavioral activity patterns of Six6-null mice under various photoperiod manipulations and stained their hypothalami using SCN-specific markers. Six6-null mice display abnormal patterns of circadian behavior indicative of SCN abnormalities. The ability of light exposure to reset rhythms correlates with the presence or absence of optic nerves, but all Six6-null mice show irregular rhythms. In contrast, wild-type mice with crushed optic nerves maintain regular rhythms regardless of light exposure. Using immunohistochemistry for arginine vasopressin (AVP), vasoactive intestinal polypeptide (VIP), and β-galactosidase, we demonstrated the lack of these SCN markers in all Six6-null mice regardless of the presence of optic nerve or partial circadian rhythms. Therefore, Six6 is required for the normal development of the SCN, and the Six6-null mouse can mount independent, although irregular, circadian rhythms despite the apparent absence of a histochemically defined SCN.
authors: Department of Reproductive Medicine, University of California, San Diego, La Jolla, CA, USA.
authors: Daniel D
authors: DD
authors: Clark
authors: Michael R
authors: MR
authors: Gorman
authors: Megumi
authors: M
authors: Hatori
authors: Jason D
authors: JD
authors: Meadows
authors: Satchidananda
authors: S
authors: Panda
authors: Pamela L
authors: PL
authors: Mellon
mesh_terms: D000818:Animals; D001127:Arginine Vasopressin / Q000378:metabolism; D002940:Circadian Rhythm / Q000502:physiology*; D018398:Homeodomain Proteins / Q000378:metabolism; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D017440:Photoperiod; D012863:Skeleton; D013493:Suprachiasmatic Nucleus / Q000378:metabolism / Q000502:physiology*; D015534:Trans-Activators / Q000172:deficiency* / Q000378:metabolism; D014660:Vasoactive Intestinal Peptide / Q000378:metabolism; D001616:beta-Galactosidase / Q000378:metabolism
chemical_list: D018398:Homeodomain Proteins; C114419:Six6 protein, mouse; D015534:Trans-Activators; D001127:Arginine Vasopressin; D014660:Vasoactive Intestinal Peptide; D001616:beta-Galactosidase
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