Divergent functions of the proneural genes Mash1 and Ngn2 in the specification of neuronal subtype identity

Abstract

The neural bHLH genes Mash1 and Ngn2 are expressed in complementary populations of neural progenitors in the central and peripheral nervous systems. Here, we have systematically compared the activities of the two genes during neural development by generating replacement mutations in mice in which the coding sequences of Mash1 and Ngn2 were swapped. Using this approach, we demonstrate that Mash1 has the capacity to respecify the identity of neuronal populations normally derived from Ngn2-expressing progenitors in the dorsal telencephalon and ventral spinal cord. In contrast, misexpression of Ngn2 in Mash1-expressing progenitors does not result in any overt change in neuronal phenotype. Taken together, these results demonstrate that Mash1 and Ngn2 have divergent functions in specification of neuronal subtype identity, with Mash1 having the characteristics of an instructive determinant whereas Ngn2 functions as a permissive factor that must act in combination with other factors to specify neuronal phenotypes. Moreover, the ectopic expression of Ngn2 can rescue the neurogenesis defects of Mash1 null mutants in the ventral telencephalon and sympathetic ganglia but not in the ventral spinal cord and the locus coeruleus, indicating that Mash1 contribution to the specification of neuronal fates varies greatly in different lineages, presumably depending on the presence of other determinants of neuronal identity. The mechanisms underlying the generation by multipotent stem cells of the vast array of neuronal and glial subtypes that constitute the nervous system remain poorly characterized. Recently, evidence have been obtained that genes of the bHLH class are important regulators of several steps in neural lineage development (Brunet and Ghysen 1999;Cepko 1999;Guillemot 1999;Morrison 2001). In particular, a subset of neural bHLH genes, the proneural genes, has been shown to play a central role in the selection of neural progenitor cells. Two families of proneural genes have been identified in Drosophila, the achaete-scute genes (ac-sc) which control the generation of progenitors for the central nervous system (CNS) and external sense organs in the peripheral nervous system (PNS), and genes of the atonal family (ato) which control the generation of progenitors for photoreceptors, chordotonal organs, and olfactory receptors (Modolell 1997;Campos-Ortega 1998). In vertebrates, a large number of bHLH genes are expressed in the developing nervous system, but only a fraction of them appear to have a proneural function. Loss-of-function (LOF) analyses in mouse have demonstrated that the ac-sc homolog Mash1 and the ato-related genes Neurogenin (Ngn) 1 and Ngn2 are required for the generation by neural stem cells of various populations of progenitor cell populations in the PNS and CNS, including progenitors in the ventral telencephalon and olfactory epithelium for Mash1, and in the cranial and dorsal root ganglia, the dorsal telencephalon and the ventral spinal cord for Ngn1 and Ngn2 (Cau et al. 1997;Fode et al. 1998Fode et al. , 2...

Differential Requirement for Nucleostemin in Embryonic Stem Cell and Neural Stem Cell Viability

“…We also confirmed that the ES cell-pluripotent marker Oct-3/4 was not expressed in these cells (data not shown), although the neural progenitor gene Mash1 [42] was detected in both cell populations (Fig. 6C).…”

Regulatory pathways linking progenitor patterning, cell fates and neurogenesis in the ventral neural tube

“…Evidence to support this has come from elegant genetic experiments analysing the role of Mash1 and Ngn2 in the ventral neural tube. Mash1 is expressed by progenitors that give rise to V2 interneurons and is required for their generation (Parras et al 2002). In contrast, Ngn2 is more broadly expressed in progenitors of MNs, V1 and V3 neurons and loss of Ngn2 results in impaired generation of these cell types (Scardigli et al 2001;Parras et al 2002).…”

In VivoAnalysis of Ascl1 Defined Progenitors Reveals Distinct Developmental Dynamics during Adult Neurogenesis and Gliogenesis

“…In the dorsal spinal cord, Ascl1 functions in specifying glutamatergic interneuron populations dI3 and dI5 (dorsal interneuron 3 and 5) (Helms et al, 2005). In telencephalon development, Ascl1 functions with Dlx2 to generate the GABAergic neurons that migrate to the cortex (Fode et al, 2000;Parras et al, 2002;Long et al, 2007). And in the peripheral nervous system, Ascl1 biases neural crest cells to the autonomic lin- eage rather than the sensory (Perez et al, 1999).…”

“…In paradigms in which Ascl1 is ectopically expressed in neural progenitor cells, the cells exit the cell cycle and begin expressing neuronal differentiation markers (Farah et al, 2000;Nakada et al, 2004). However, within a particular spatial and temporal context, Ascl1 appears to play a role in the specification of neuronal subtype as seen in interneuron formation in the spinal cord (Nakada et al, 2004;Helms et al, 2005) and cortex (Fode et al, 2000;Parras et al, 2002), and in sympathetic neurons during neural crest development (Perez et al, 1999). Thus, Ascl1 is an important regulator of neuronal differentiation and subtype specification in the developing central and peripheral nervous systems.…”