title: Targeted mutation of the calbindin D28K gene disrupts circadian rhythmicity and entrainment.
abstract: The suprachiasmatic nucleus (SCN) is the principal circadian pacemaker in mammals. A salient feature of the SCN is that cells of a particular phenotype are topographically organized; this organization defines functionally distinct subregions that interact to generate coherent rhythmicity. In Syrian hamsters (Mesocricetus auratus), a dense population of directly retinorecipient calbindin D(28K) (CalB) neurons in the caudal SCN marks a subregion critical for circadian rhythmicity. In mouse SCN, a dense cluster of CalB neurons occurs during early postnatal development, but in the adult CalB neurons are dispersed through the SCN. In the adult retina CalB colocalizes with melanopsin-expressing ganglion cells. In the present study, we explored the role of CalB in modulating circadian function and photic entrainment by investigating mice with a targeted mutation of the CalB gene (CalB-/- mice). In constant darkness (DD), CalB-/- animals either become arrhythmic (40%) or exhibit low-amplitude locomotor rhythms with marked activity during subjective day (60%). Rhythmic clock gene expression is blunted in these latter animals. Importantly, CalB-/- mice exhibit anomalies in entrainment revealed following transfer from a light : dark cycle to DD. Paradoxically, responses to acute light pulses measured by behavioral phase shifts, SCN FOS protein and Period1 mRNA expression are normal. Together, the developmental pattern of CalB expression in mouse SCN, the presence of CalB in photoresponsive ganglion cells and the abnormalities seen in CalB-/- mice suggest an important role for CalB in mouse circadian function.
authors.affiliation: Department of Psychology and Helen Wills Neuroscience Institute, 3210 Tolman Hall, University of California, Berkeley, CA 94720, USA. kriegsfeld@berkeley.edu
authors.forename: Lance J
authors.initials: LJ
authors.lastname: Kriegsfeld
authors.forename: Dan Feng
authors.initials: DF
authors.lastname: Mei
authors.forename: Lily
authors.initials: L
authors.lastname: Yan
authors.forename: Paul
authors.initials: P
authors.lastname: Witkovsky
authors.forename: Joseph
authors.initials: J
authors.lastname: Lesauter
authors.forename: Toshiyuki
authors.initials: T
authors.lastname: Hamada
authors.forename: Rae
authors.initials: R
authors.lastname: Silver
mesh_terms: D000221:Adaptation, Ocular / Q000235:genetics; D000818:Animals; D064092:Calbindin 1; D064026:Calbindins; D020013:Calcium Signaling / Q000235:genetics; D018797:Cell Cycle Proteins / Q000235:genetics; D002940:Circadian Rhythm / Q000235:genetics* / Q000528:radiation effects; D003623:Dark Adaptation / Q000235:genetics; D005786:Gene Expression Regulation / Q000235:genetics; D018390:Gene Targeting / Q000379:methods; D008027:Light; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D009043:Motor Activity / Q000235:genetics / Q000528:radiation effects; D009154:Mutation / Q000235:genetics*; D009687:Nuclear Proteins / Q000235:genetics; D056950:Period Circadian Proteins; D010775:Photic Stimulation; D017440:Photoperiod; D016760:Proto-Oncogene Proteins c-fos / Q000378:metabolism; D012333:RNA, Messenger / Q000378:metabolism; D064030:S100 Calcium Binding Protein G / Q000235:genetics*; D013493:Suprachiasmatic Nucleus / Q000378:metabolism* / Q000528:radiation effects
chemical_list: C576499:Calb1 protein, mouse; D064092:Calbindin 1; D064026:Calbindins; D018797:Cell Cycle Proteins; D009687:Nuclear Proteins; C539023:Per1 protein, mouse; D056950:Period Circadian Proteins; D016760:Proto-Oncogene Proteins c-fos; D012333:RNA, Messenger; D064030:S100 Calcium Binding Protein G