Ascl1 and Helt act combinatorially to specify thalamic neuronal identity by repressing Dlxs activation

Abstract

The mammalian thalamus is an essential diencephalic derivative that plays unique roles in processing and relaying sensory and motor information to and from the cerebral cortex. The profile of transcription factors and lineage tracing experiments revealed a spatiotemporal relationship between diencephalic progenitor domains and discrete differentiated neurons contributing to thalamic nuclei. However, the precise molecular mechanisms by which heterogeneous thalamic neurons become specified and assemble into distinct thalamic nuclei are still poorly understood. Here, we show that a combinatorial interaction between the bHLH transcription factors Ascl1 and Helt is required for acquiring thalamic progenitor identity. Surprisingly, in the combined absence of Ascl1 and Helt, rostral thalamic progenitors (TH-R) adopt a molecular profile of a more rostral diencephalic derivative, the prethalamus. Furthermore, we show that the prethalamic factors Dlxs upregulated by Ascl1/Helt deficiency play unique roles in regulating thalamic progenitor specification, and that derepression of Dlx2 and Dlx5 suppress generation of TH-R neurons. Taken together, our results suggest a model whereby the combined activity of two distinct bHLH factors plays a key role in the development of discrete classes of thalamic interneurons.

Tectal-derived interneurons contribute to phasic and tonic inhibition in the visual thalamus

“…GABAergic progenitors in p3, including those of the RTN, express Ascl1 and progress through a differentiation programme that depends on Dlx1 , Dlx2 and Arx (refs 11, 16, 17, 18, 19, 20, 21). GABAergic neurogenesis in pTh-R requires interaction between the pan-GABAergic proneural transcription factor Ascl1 and the GABAergic subtype-specific transcription factor Helt16.…”

“…GABAergic progenitors in p3, including those of the RTN, express Ascl1 and progress through a differentiation programme that depends on Dlx1 , Dlx2 and Arx (refs 11, 16, 17, 18, 19, 20, 21). GABAergic neurogenesis in pTh-R requires interaction between the pan-GABAergic proneural transcription factor Ascl1 and the GABAergic subtype-specific transcription factor Helt16. Ascl1-Helt dimerization leads to sequential activation of other transcription factor genes, including Gata2 , Tal1 , Tal2 , Gata3 and Sox14 (refs 16, 17, 18, 19, 22, 23, 24), all of which are also found in the first diencephalic prosomere (p1, also known as the pretectum), but not in p3.…”

“…GABAergic neurogenesis in pTh-R requires interaction between the pan-GABAergic proneural transcription factor Ascl1 and the GABAergic subtype-specific transcription factor Helt16. Ascl1-Helt dimerization leads to sequential activation of other transcription factor genes, including Gata2 , Tal1 , Tal2 , Gata3 and Sox14 (refs 16, 17, 18, 19, 22, 23, 24), all of which are also found in the first diencephalic prosomere (p1, also known as the pretectum), but not in p3. Furthermore, reciprocal repression between Dlx1/2 and Gata2/3 suggests that alternative GABA fates are acquired in p3 and pTh-R (refs 17, 18, 19).…”

Ascl1 promotes tangential migration and confines migratory routes by induction of Ephb2 in the telencephalon

“…Interestingly, Ascl1 may regulate the expression of Dlx1/2 negatively or positively 44,45 . In the ventral telencephalon, Ascl1 maintains the pool of neural progenitors at least in part by regulating the Notch pathway 42 .…”

“…Loss of Ascl1 leads to premature neuronal differentiation and expansion of Dlx1/2 expression domain 19,42 . In the developing thalamus, Ascl1 represses Dlx1/2 expression through Helt, a bHLH-Orange factor, to specify GABAergic neurons from thalamic progenitors 45 . These findings suggest that Ascl1 acts as a negative regulator for Dlx1/2 expression in some cellular contexts.…”