Abstract
In contrast with the wealth of data involving bHLH and homeodomain transcription factors in retinal cell type determination, the molecular bases underlying neurotransmitter subtype specification is far less understood. Using both gain and loss of function analyses in Xenopus, we investigated the putative implication of the bHLH factor Ascl1 in this process. We found that in addition to its previously characterized proneural function, Ascl1 also contributes to the specification of the GABAergic phenotype. We showed that it is necessary for retinal GABAergic cell genesis and sufficient in overexpression experiments to bias a subset of retinal precursor cells towards a GABAergic fate. We also analysed the relationships between Ascl1 and a set of other bHLH factors using an in vivo ectopic neurogenic assay. We demonstrated that Ascl1 has unique features as a GABAergic inducer and is epistatic over factors endowed with glutamatergic potentialities such as Neurog2, NeuroD1 or Atoh7. This functional specificity is conferred by the basic DNA binding domain of Ascl1 and involves a specific genetic network, distinct from that underlying its previously demonstrated effects on catecholaminergic differentiation. Our data show that GABAergic inducing activity of Ascl1 requires the direct transcriptional regulation of Ptf1a, providing therefore a new piece of the network governing neurotransmitter subtype specification during retinogenesis.
Highlights
During development, neural specification leads to the emergence of a large diversity of neuronal subtypes that will serve distinct functions in the adult nervous system
We examined the effect of Ascl1 loss-of-function by analysing the expression of gad1 and VGlut1, which respectively encode the rate-limiting enzyme for GABA biosynthesis and a glutamate transporter expressed in neurons
We observed in Ascl1-Mo injected retinas that the different glutamatergic neuronal populations were unevenly affected, with VGlut1 expression being largely unchanged in ganglion cells, reduced in the photoreceptor layer, while appearing expanded in the inner nuclear layer (INL) (Fig. 1G, H)
Summary
Neural specification leads to the emergence of a large diversity of neuronal subtypes that will serve distinct functions in the adult nervous system. A small number of basic helix-loop-helix (bHLH) transcription factors are necessary and sufficient for progenitor cell commitment towards a neuronal lineage at the expense of a glial fate and have been qualified as ‘‘proneural genes’’ [1] Beside their generic function, several studies have shown that proneural genes display context-dependent effects contributing to the differentiation of particular neuronal subtypes [1,2]. Several studies have shown that proneural genes display context-dependent effects contributing to the differentiation of particular neuronal subtypes [1,2] This is the case for the atonal-related neurogenin genes (Neurog and Neurog2) and the achaete scute gene Ascl (achaete-scute complex homolog 1; called Mash in mouse or Xash in Xenopus). Exploring its involvement in other nervous system regions, such as the retina, and unravelling how it integrates within distinct genetic networks are required to better understand its divergent properties
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