Graded Otx2 activities demonstrate dose-sensitive eye and retina phenotypes.
In the human, mutations of OTX2 (Orthodenticle homeobox 2 transcription factor) translate into eye malformations of variable expressivity (even between the two eyes of the same individual) and incomplete penetrance, suggesting the existence of subtle thresholds in OTX2 activity. We have addressed this issue by analyzing retinal structure and function in six mutant mice with graded Otx2 activity: Otx2(+/+), Otx2(+/AA), Otx2(+/GFP), Otx2(AA/AA), Otx2(AA/GFP) and Otx2(GFP/GFP). Null mice (Otx2(GFP/GFP)) fail to develop the head and are embryonic lethal, and compound heterozygous Otx2(AA/GFP) mice show a truncated head and die at birth. All other genotypes develop until adulthood. We analyzed eye structure and visual physiology in the genotypes that develop until adulthood and report that phenotype severity parallels Otx2 activity. Otx2(+/AA) are only mildly affected whereas Otx2(+/GFP) are more affected than Otx2(+/AA) but less than Otx2(AA/AA) mice. Otx2(AA/AA) mice later manifest the most severe defects, with variable expressivity. Electrophysiological and histological analyses of the mouse retina revealed progressive death of bipolar cells and cone photoreceptors that is both Otx2 activity- and age-dependent with the same ranking of phenotypic severity. This study demonstrates the importance of gene dosage in the development of age-dependent pathologies and underscores the fact that small gene dosage differences can cause significant pathological states.
Collège de France, Center for Interdisciplinary Research in Biology, UMR CNRS 7241/INSERM U1050, 11 place Marcelin Berthelot, Paris 75005, France.
Clémence
C
Bernard
Hyoung-Tai
HT
Kim
Raoul
R
Torero Ibad
Eun Jung
EJ
Lee
Manuel
M
Simonutti
Serge
S
Picaud
Dario
D
Acampora
Antonio
A
Simeone
Ariel A
AA
Di Nardo
Alain
A
Prochiantz
Kenneth L
KL
Moya
Jin Woo
JW
Kim
D000818:Animals; D002454:Cell Differentiation / Q000235:genetics; D002460:Cell Line; D005124:Eye Abnormalities / Q000235:genetics*; D018628:Gene Dosage; D018507:Gene Expression Regulation, Developmental; D049452:Green Fluorescent Proteins / Q000235:genetics; D051379:Mice; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D051857:Otx Transcription Factors / Q000235:genetics*; D019683:Penetrance; D051245:Retinal Bipolar Cells / Q000166:cytology*; D017949:Retinal Cone Photoreceptor Cells / Q000166:cytology*; D051248:Retinal Horizontal Cells / Q000166:cytology*; D014792:Visual Acuity / Q000235:genetics
D051857:Otx Transcription Factors; C497660:Otx2 protein, mouse; D049452:Green Fluorescent Proteins