Loss of circadian photoentrainment and abnormal retinal electrophysiology in Math5 mutant mice.
OBJECTIVE
To determine how the absence of retinal ganglion cells (RGCs) in Math5 (Atoh7) mutant mice affects circadian behavior and retinal function.


METHODS
The wheel-running behavior of wild-type and Math5 mutant mice was measured under various light-dark cycle conditions. To evaluate retinal input to the suprachiasmatic nuclei (SCN) anatomically, the retinohypothalamic tracts were labeled in vivo. To assess changes in retinal function, corneal flash electroretinograms (ERGs) from mutant and wild-type mice were compared under dark- and light-adapted conditions. Alterations in retinal neuron populations were evaluated quantitatively and with cell-type-specific markers.


RESULTS
The Math5-null mice did not entrain to light and exhibited free-running circadian behavior with a mean period (23.6 +/- 0.15 hours) that was indistinguishable from that of wild-type mice (23.4 +/- 0.19 hours). The SCN showed no anterograde labeling with a horseradish peroxidase-conjugated cholera toxin B (CT-HRP) tracer. ERGs recorded from mutant mice had diminished scotopic a- and b-wave and photopic b-wave amplitudes. The scotopic b-wave was more severely affected than the a-wave. The oscillatory potentials (OPs) and scotopic threshold response (STR) were also reduced. Consistent with these ERG findings, a pan-specific reduction in the number of bipolar cells and a smaller relative decrease in the number of rods in mutant mice were observed.


CONCLUSIONS
Math5-null mice are clock-blind and have no RGC projections to the SCN. RGCs are thus essential for photoentrainment in mice, but are not necessary for the development or intrinsic function of the SCN clock. RGCs are not required to generate any of the major ERG waveforms in mice, including the STR, which is produced by ganglion cells in some other species. The diminished amplitude of b-wave, OPs, and STR components in Math5 mutants is most likely caused by the decreased abundance of retinal interneurons.
Department of Human Genetics, University of Michigan, Ann Arbor, 48109, USA.
Joseph A
JA
Brzezinski
Nadean L
NL
Brown
Atsuhiro
A
Tanikawa
Ronald A
RA
Bush
Paul A
PA
Sieving
Martha H
MH
Vitaterna
Joseph S
JS
Takahashi
Tom
T
Glaser
D000818:Animals; D051792:Basic Helix-Loop-Helix Proteins; D021081:Chronobiology Disorders / Q000503:physiopathology*; D002940:Circadian Rhythm; D003623:Dark Adaptation; D004594:Electrophysiology; D004596:Electroretinography; D018257:Helix-Loop-Helix Motifs / Q000502:physiology; D007395:Interneurons / Q000502:physiology; D008027:Light; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D008817:Mice, Mutant Strains; D018613:Microscopy, Confocal; D009419:Nerve Tissue Proteins / Q000172:deficiency* / Q000235:genetics; D017440:Photoperiod; D012160:Retina / Q000503:physiopathology*; D012162:Retinal Degeneration / Q000235:genetics / Q000378:metabolism / Q000503:physiopathology*; D012165:Retinal Ganglion Cells / Q000378:metabolism / Q000473:pathology*; D013493:Suprachiasmatic Nucleus / Q000502:physiology; D014157:Transcription Factors / Q000172:deficiency* / Q000235:genetics; D014795:Visual Pathways / Q000502:physiology
D051792:Basic Helix-Loop-Helix Proteins; D009419:Nerve Tissue Proteins; D014157:Transcription Factors; C117638:Atoh7 protein, mouse