Loss of LMO4 in the retina leads to reduction of GABAergic amacrine cells and functional deficits.
BACKGROUND
LMO4 is a transcription cofactor expressed during retinal development and in amacrine neurons at birth. A previous study in zebrafish reported that morpholino RNA ablation of one of two related genes, LMO4b, increases the size of eyes in embryos. However, the significance of LMO4 in mammalian eye development and function remained unknown since LMO4 null mice die prior to birth.


RESULTS
We observed the presence of a smaller eye and/or coloboma in ∼40% LMO4 null mouse embryos. To investigate the postnatal role of LMO4 in retinal development and function, LMO4 was conditionally ablated in retinal progenitor cells using the Pax6 alpha-enhancer Cre/LMO4flox mice. We found that these mice have fewer Bhlhb5-positive GABAergic amacrine and OFF-cone bipolar cells. The deficit appears to affect the postnatal wave of Bhlhb5+ neurons, suggesting a temporal requirement for LMO4 in retinal neuron development. In contrast, cholinergic and dopaminergic amacrine, rod bipolar and photoreceptor cell numbers were not affected. The selective reduction in these interneurons was accompanied by a functional deficit revealed by electroretinography, with reduced amplitude of b-waves, indicating deficits in the inner nuclear layer of the retina.


CONCLUSIONS
Inhibitory GABAergic interneurons play a critical function in controlling retinal image processing, and are important for neural networks in the central nervous system. Our finding of an essential postnatal function of LMO4 in the differentiation of Bhlhb5-expressing inhibitory interneurons in the retina may be a general mechanism whereby LMO4 controls the production of inhibitory interneurons in the nervous system.
Duquette
Philippe M
PM
Centre for Stroke Recovery, Neuroscience, Ottawa Hospital Research Institute, Ottawa, Ontario, Canada.
Zhou
Xun
X
Yap
Nida Lerma
NL
MacLaren
Erik J
EJ
Lu
Jesse J
JJ
Wallace
Valerie A
VA
Chen
Hsiao-Huei
HH
D048868:Adaptor Proteins, Signal Transducing; D000818:Animals; D001483:Base Sequence; D017931:DNA Primers; D004742:Enhancer Elements, Genetic; D018398:Homeodomain Proteins / Q000235:genetics / Q000502:physiology*; D007150:Immunohistochemistry; D017403:In Situ Hybridization; D060588:LIM Domain Proteins; D051379:Mice; D008810:Mice, Inbred C57BL; D011401:Promoter Regions, Genetic; D012160:Retina / Q000166:cytology / Q000254:growth & development / Q000378:metabolism* / Q000502:physiology; D014157:Transcription Factors / Q000235:genetics / Q000502:physiology*; D005680:gamma-Aminobutyric Acid / Q000378:metabolism*
D048868:Adaptor Proteins, Signal Transducing; D017931:DNA Primers; D018398:Homeodomain Proteins; D060588:LIM Domain Proteins; C491976:Lmo4 protein, mouse; D014157:Transcription Factors; D005680:gamma-Aminobutyric Acid