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L. Gan; Barhl2 Is Required for the Formation of the Displaced Cholinergic Amacrine Mosaic in Mouse Retina. Invest. Ophthalmol. Vis. Sci. 2010;51(13):1851.
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© ARVO (1962-2015); The Authors (2016-present)
In the central nervous system, neurons of the same type are often distributed in nonrandom fashions or mosaics. Currently, little is known about how these mosaics are generated during development. The purpose of this study is to identify the genetic pathway(s) regulating the mosaic formation in the retina.
We generated mice with a null mutation in the BarH homeodomain gene Barhl2 by knocking-in Cre recombinase gene into Barhl2 locus and performed phenotype and lineage analyses of Barhl2-expressing cells using conditional GFP reporter (Z/EG) mouse lines. The cells from Barhl2-lineage were permanently marked by the expression of GFP in normal and Barhl2-null retinas, and the identities of these cells were characterized using retinal cell type-specific antibodies.
During normal retinal development, Barhl2 is expressed in selected groups (subtypes) of retinal ganglion cells (RGCs) and amacrine cells (ACs). Targeted deletion of Barhl2 resulted in a significant reduction of glycinergic and GABAergic ACs accompanied by a substantial increase in the number of choline acetyltransferase (ChAT) ACs in Barhl2-null retinas. In the absence of Barhl2, all RGCs of Barhl2-lineage underwent apoptosis during embryonic development. Additionally, in the ganglion cell layer (GCL), the displaced ChAT+ ACs were significantly increased in Barhl2-nulls and strikingly, the normal spatial distribution of these ChAT+ ACs was severely disrupted.
Barhl2 plays important roles in retinal development by regulating of RGC and AC subtype specification, differentiation, and survival. The loss of the ChAT+ AC mosaic in Barhl2-null retina implicates BARHL2 as the first known transcription factor with a role in establishing the neuronal mosaic.
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