Abstract
BackgroundIn recent years, considerable knowledge has been gained on the molecular mechanisms underlying retinal cell fate specification. However, hitherto studies focused primarily on the six major retinal cell classes (five types of neurons of one type of glial cell), and paid little attention to the specification of different neuronal subtypes within the same cell class. In particular, the molecular machinery governing the specification of the two most abundant neurotransmitter phenotypes in the retina, GABAergic and glutamatergic, is largely unknown. In the spinal cord and cerebellum, the transcription factor Ptf1a is essential for GABAergic neuron production. In the mouse retina, Ptf1a has been shown to be involved in horizontal and most amacrine neurons differentiation.ResultsIn this study, we examined the distribution of neurotransmitter subtypes following Ptf1a gain and loss of function in the Xenopus retina. We found cell-autonomous dramatic switches between GABAergic and glutamatergic neuron production, concomitant with profound defects in the genesis of amacrine and horizontal cells, which are mainly GABAergic. Therefore, we investigated whether Ptf1a promotes the fate of these two cell types or acts directly as a GABAergic subtype determination factor. In ectodermal explant assays, Ptf1a was found to be a potent inducer of the GABAergic subtype. Moreover, clonal analysis in the retina revealed that Ptf1a overexpression leads to an increased ratio of GABAergic subtypes among the whole amacrine and horizontal cell population, highlighting its instructive capacity to promote this specific subtype of inhibitory neurons. Finally, we also found that within bipolar cells, which are typically glutamatergic interneurons, Ptf1a is able to trigger a GABAergic fate.ConclusionAltogether, our results reveal for the first time in the retina a major player in the GABAergic versus glutamatergic cell specification genetic pathway.
Highlights
In recent years, considerable knowledge has been gained on the molecular mechanisms underlying retinal cell fate specification
Altogether, our results reveal for the first time in the retina a major player in the GABAergic versus glutamatergic cell specification genetic pathway
At stage 41, when all cells in the central retina are post-mitotic, Ptf1a expression became restricted to the ciliary marginal zone (CMZ), the only retinal region where retinogenesis is still occurring post-embryonically (Fig. 1L)
Summary
Considerable knowledge has been gained on the molecular mechanisms underlying retinal cell fate specification. Previous studies have established that these distinct retinal cell types are specified through a combinatorial code of bHLH and homeodomain transcription factors [5,7,8,9]. Amacrine cells, which modulate synaptic activity between bipolar and ganglion cells, constitute the most diverse cell type within the retina [10,11] In mammals, they can be further classified into 29 different amacrine subtypes based on criteria such as sub-laminar localization (the inner plexiform layer, the ganglion cell layer and the inner part of the inner nuclear layer), morphology (e.g. starburst, parasol or midget) and neurotransmitter type (e.g. GABAergic, glycinergic, dopaminergic or serotoninergic) [11]. The number of amacrine subtype cells stands at no less than 21 [13]
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