Phox2b and motoneuronal differentiation

The specification of neuronal subtype identity in the developing central nervous system (CNS) appears to be controlled by the interplay between inductive signals secreted by embryonic signaling centers and the transcription factors that transmit this information onto the transcriptional apparatus (Lumsden and Krumlauf, 1996; Edlund and Jessell, 1999). A large number of different transcription factors have been found to be expressed in the developing CNS in discrete temporal and regionor cell-type-specific patterns. They are thought to control the generation of neuronal cell type diversity, in complex combinations and sequences. A major challenge is to assemble an integrated picture of this transcriptional logic of neuronal type-specific differentiation. In vertebrates, motor neurons represent one of the betterunderstood model systems for exploring the molecular mechanisms that specify neuronal fate. Three general classes of motor neurons are found in the spinal cord and hindbrain: the somatic motor (sm) neurons that innervate most skeletal muscles in the body, the branchiomotor (bm) neurons that innervate muscles derived from the branchial arches, and visceral motor (vm) neurons that innervate sympathetic and parasympathetic ganglia. Sm neurons differentiate from progenitors in the ventral half of the neural tube characterized by the expression of the homeobox gene Pax6; bm and vm neurons in the hindbrain arise ventral to the former from progenitors that express the homeobox genes Nkx2.2 and Nkx2.9 (Ericson et al., 1997; Briscoe et al., 1999). Generation of sm neurons has been studied most extensively and some of the transcriptional cascades controlling their differentiation are beginning to be understood. Pax6 activity is required for sm differentiation, but appears to act mainly by suppressing expression of Nkx2.2. In the hindbrain, lack of Pax6 diverts sm neurons towards a vm fate (Ericson et al., 1997; Osumi et al., 1997). Studies in chick embryos have implicated the homeobox genes MNR2 and its close homologue HB9 in sm differentiation (Tanabe et al., 1998). MNR2 is switched on by sm progenitors just before their final division, whereas HB9 is expressed during further differentiation. When misexpressed in neural tube cells, both MNR2 and HB9 are able to instruct the sm phenotype. A separate line of research has concentrated on the acquisition of generic neuronal properties. In vertebrates, many genes that are related to the Drosophila proneural genes and encode bHLH transcription factors, have been found to be expressed in the developing nervous system; a number of them have been shown to have proneural activity, in that they induce formation of ectopic or supernumerary neurons when overexpressed in Xenopus embryos (see Anderson and Jan, 1997; Brunet and Ghysen, 1999 for review). Using this type of analysis and loss-of-function experiments in the mouse (Fode et al., 1998; Ma et al., 1998), it has been possible to place them in epistatic cascades, those expressed in dividing progenitors (such as the Neurogenins and Mash1) driving the expression of downstream genes activated at later stages of differentiation (such as NeuroD and Math3). These factors have thus been studied mostly for their capacity to induce a generic neuronal 1349 Development 127, 1349-1358 (2000) Printed in Great Britain © The Company of Biologists Limited 2000 DEV1515