The Hes family of basic helix-loop-helix (bHLH) transcriptional repressors (Hes1, Hes3 and Hes5) function downstream of Notch signaling (Kageyama and Ohtsuka, 1999), strongly inhibit neuronal differentiation, and maintain NSCs in the developing mammalian brain by repressing the proneural (neurogenic) bHLH factors such as Ascl1 and Neurog1/2 (Ishibashi et al., 1994; Ohtsuka et al., 1999, 2001; Hirata et al., 2000; Hatakeyama et al., 2004). Hes1 single mutant mice demonstrate severe phenotypes caused by accelerated neuronal differentiation, whereas Hes3 or Hes5 mutant mice exhibit only mild phenotypes owing to compensation by upregulated Hes1.
It is thus likely that Hes1 is an essential and dominant factor among the Hes family of repressors that maintains NSCs in an undifferentiated state.
Nervous systems are composed of a diverse array of neuronal cell types that form functional circuits. This cellular complexity is generated by the combinatorial activity of transcription factors (TFs). Decades of developmental biology studies identified a handful of basic helix-loop-helix (bHLH) TFs called “proneural factors” that are necessary and sufficient to initiate neurogenesis.
Ascl1 (Mash1) and Neurogenin2 (Neurog2), which are the mammalian homologs of Drosophila achaete-scute complex and atonal, respectively, are the two main proneural factors that initiate and regulate neurogenesis in vertebrate nervous systems. Apart from a few regions in the nervous system where they are co-expressed, these two proneural factors are expressed in a complementary manner and are not interchangeable for neuronal subtype specification. Proneural factors promote neurogenesis and induce distinct subtype identities, and these functions are conserved across phyla. In Drosophila ectoderm atonal controls chordotonal organ identity, while achaete-scute genes control external sensory organs8. In mice, Ascl1 and Neurog2 are respectively required to specify GABAergic (inhibitory) and glutamatergic (excitatory) neurons in the forebrain and sympathetic and sensory neurons of the peripheral nervous system. Thus, functional divergence of Ascl1 and Neurog2 is an ancestral trait responsible for the generation of neuronal diversity required in the nervous system which predates the split of vertebrates and invertebrates15.
