Loss of photic entrainment and altered free-running circadian rhythms in math5-/- mice.
Mammalian free-running circadian rhythms are entrained to the external light/dark cycle by photic signaling to the suprachiasmatic nuclei via the retinohypothalamic tract (RHT). We investigated the circadian entrainment and clock properties of math5-/- mutant mice. math5 is a critical regulator of retinal ganglion cell development; math5-/- mice show severe optic nerve hypoplasia. By anterograde cholera toxin B tracing, we find that math5-/- mice do not develop an identifiable RHT pathway. This appears to be attributable to agenesis or dysgenesis of the majority of RHT-projecting retinal ganglion cells. math5-/- mice display free-running circadian rhythms with a period approximately 1 hr longer than B6/129 controls (24.43 +/- 0.10 vs 23.62 +/- 0.19 hr; p < 0.00001). The free-running period of heterozygote mice is indistinguishable from that of controls. math5-/- mice show no entrainment to light/dark cycles, whereas heterozygote mice show normal entrainment to both 12 hr light/dark cycles and to a 1 hr skeletal photoperiod. math5-/- mice show reduced ability to entrain their rhythms to the nonphotic time cue of restricted running wheel access but demonstrate both free-running behavior and entrained anticipation of wheel unlocking in these conditions, suggesting the presence of a second diurnal oscillatory system in math5-/- animals. These results demonstrate that retinal ganglion cell input is not necessary for the development of a free-running circadian timekeeping system in the suprachiasmatic nucleus but is important for both photic entrainment and determination of the free-running period.
Wee
Raymond
R
Department of Ophthalmology and Visual Sciences, Washington University Medical School, St. Louis, Missouri 63110, USA.
Castrucci
Ana Maria
AM
Provencio
Ignacio
I
Gan
Lin
L
Van Gelder
Russell N
RN
D000818:Animals; D051792:Basic Helix-Loop-Helix Proteins; D021081:Chronobiology Disorders / Q000235:genetics / Q000503:physiopathology*; D002940:Circadian Rhythm / Q000235:genetics / Q000502:physiology; D003624:Darkness; D006579:Heterozygote; D006720:Homozygote; D008027:Light; D051379:Mice; D008815:Mice, Inbred Strains; D018345:Mice, Knockout; D009043:Motor Activity / Q000502:physiology*; D009419:Nerve Tissue Proteins / Q000172:deficiency* / Q000235:genetics; D010775:Photic Stimulation / Q000379:methods*; D017440:Photoperiod; D012165:Retinal Ganglion Cells / Q000166:cytology / Q000378:metabolism; D017299:Rod Opsins / Q000096:biosynthesis; D013997:Time Factors; D014157:Transcription Factors / Q000172:deficiency* / Q000235:genetics; D014795:Visual Pathways / Q000033:anatomy & histology / Q000502:physiology; D000099210:Melanopsin
D051792:Basic Helix-Loop-Helix Proteins; D009419:Nerve Tissue Proteins; D017299:Rod Opsins; D014157:Transcription Factors; D000099210:Melanopsin; C117638:Atoh7 protein, mouse