Crossregulation between Neurogenin2 and Pathways Specifying Neuronal Identity in the Spinal Cord (original) (raw)

subsequently by the floor plate (reviewed in . Shh acts in a concentration-dependent manner to both induce the expression of some homeodomain proteins (e.g., Nkx2.2 and Nkx6.1) and repress that of others (e.g., Pax6, Irx3, Dbx2). The expression of specific Raffaella Scardigli, Carol Schuurmans, Gé rard Gradwohl, and Franç ois Guillemot 1 Institut de Gé né tique et de Biologie Molé culaire et Cellulaire CNRS/INSERM/Université Louis Pasteur combinations of homeodomain proteins at different DV B.P. 163 levels of the neural tube results in the establishment of 67404 Illkirch Cé dex distinct progenitor domains which give rise to particular C.U. de Strasbourg classes of neurons. The function of these early ex-France pressed homeodomain proteins in specifying neuronal fates is thought to be relayed through the action of another set of homeodomain proteins that are ex-Summary pressed by progenitor cells as they exit the cell cycle and begin to differentiate (Briscoe et al., 2000; Jessell, We have examined how genetic pathways that specify 2000). Among these are MNR2 and Hb9, two related neuronal identity and regulate neurogenesis interface factors that have been implicated in the specification of in the vertebrate neural tube. Here, we demonstrate MN identity in chick (Tanabe et al., 1998) and in mouse that expression of the proneural gene Neurogenin2 (Arber et al., 1999; Thaler et al., 1999), and Lim3, which (Ngn2) in the ventral spinal cord results from the moduis involved in the specification of V2 interneurons and lar activity of three enhancers active in distinct progena subtype of MNs (Sharma et al., 1998). itor domains, suggesting that Ngn2 expression is con-Members of the basic helix-loop-helix (bHLH) class trolled by dorsoventral patterning signals. Consistent of transcription factors play essential roles in lineage with this hypothesis, Ngn2 enhancer activity is dependetermination and in the differentiation of neural progendent on the function of Pax6, a homeodomain facitors (Kageyama and Nakanishi, 1997; Guillemot, 1999). tor involved in specifying the identity of ventral spinal Pioneering studies in Drosophila have demonstrated cord progenitors. Moreover, we show that Ngn2 is rethat proneural genes of the achaete-scute complex and quired for the correct expression of Pax6 and several atonal confer neural competence to ectodermal cells homeodomain proteins expressed in defined neuronal and control the selection of individual neural precursors populations. Thus, neuronal differentiation involves from clusters of initially equivalent cells (Jan and Jan, crossregulatory interactions between a bHLH-driven 1994). Loss-and gain-of-function studies have provided program of neurogenesis and genetic pathways specievidence that vertebrate homologs of the fly proneural fying progenitor and neuronal identity in the spinal genes function in a similar manner. For example, the cord. murine achaete-scute homolog Mash1 is required for the generation of neural progenitors in the ventral fore-Introduction brain and olfactory epithelium (Cau et al., 1997; Casarosa et al., 1999). Similarly, the atonal-related genes Progenitor populations located in different regions of the Neurogenin1 (Ngn1) and Neurogenin2 (Ngn2) are reneural tube undergo distinct programs of neurogenesis, quired for the generation of progenitors of cranial sengiving rise to specific neuronal subtypes at precise desory ganglia (Fode et al., 1998; Ma et al., 1998), while velopmental times (McConnell, 1995). The molecular the atonal ortholog Math1 is required for the generation pathways that control the generation and differentiation of cerebellar granular cells (Ben-Arie et al., 1997). of neurons and the specification of their identity are In addition to these early functions in the determinastarting to be unraveled (Edlund and Jessell, 1999). It tion of neural lineages, proneural genes have been impliremains unclear, however, how these pathways are intecated in the specification of neuronal phenotypes in grated to yield the highly diverse and reproducible patboth Drosophila and vertebrates (Jan and Jan, 1994; terns of neuronal differentiation that characterize the Jarman and Ahmed, 1998; Brunet and Ghysen, 1999; developing neural tube (Tanabe and Jessell, 1996; An-Guillemot, 1999). In vertebrates, Mash1, Math1, and the derson and Jan, 1997). Ngns are expressed in largely nonoverlapping popula-The question of how different classes of neurons are tions of progenitor cells that give rise to different types generated at distinct positions in the nervous system of neurons. In the peripheral nervous system (PNS), has been best addressed in the ventral spinal cord Mash1 is expressed in progenitors of autonomic neu-(Briscoe et al., 2000). Motor neurons (MNs) and inrons where it controls the acquisition of a noradrenergic terneurons are derived from progenitor cell populations neurotransmission phenotype. This occurs through the located at defined positions along the dorsoventral (DV) regulation by Mash1 of the expression of Phox2a, a axis of the neural tube. The DV identity of progenitor homeodomain protein that controls noradrenergic difcells in the ventral spinal cord is specified in response ferentiation by directly regulating the expression of the to graded concentrations of Sonic hedgehog (Shh), a catecholamine biosynthetic enzymes tyrosine hydroxymorphogen that is secreted first by the notochord and lase and dopamine ␤-hydroxylase (Lo et al., 1997; Hirsch et al., 1998; Goridis and Brunet, 1999). Expression of the Ngns in the PNS is complementary to that of Mash1 1 Correspondence: francois@igbmc.u-strasbg.fr Neuron 204