Ikaros-1 couples cell cycle arrest of late striatal precursors with neurogenesis of enkephalinergic neurons.

During central nervous system development, several transcription factors regulate the differentiation of progenitor cells to postmitotic neurons. Here we describe a novel role for Ikaros-1 in the generation of late-born striatal neurons. Our results show that Ikaros-1 is expressed in the boundary of the striatal germinal zone (GZ)/mantle zone (MZ), where it induces cell cycle arrest of neural progenitors by up-regulation of the cyclin-dependent kinase inhibitor (CDKi) p21(Cip1/Waf1). This effect is coupled with the neuronal differentiation of late precursors, which in turn is critical for the second wave of striatal neurogenesis that gives rise to matrix neurons. Consistently, Ikaros(-/-) mice had fewer striatal projecting neurons and, in particular, enkephalin (ENK)-positive neurons. In addition, overexpression of Ikaros-1 in primary striatal cultures increases the number of calbindin- and ENK-positive neurons. Our results also show that Ikaros-1 acts downstream of the Dlx family of transcription factors, insofar as its expression is lost in Dlx1/2 double knockout mice. However, we demonstrate that Ikaros-1 and Ebf-1 independently regulate the final determination of the two populations of striatal projection neurons of the matrix compartment, ENK- and substance P-positive neurons. In conclusion, our findings identify Ikaros-1 as a modulator of cell cycle exit of neural progenitors that gives rise to the neurogenesis of ENK-positive striatal neurons.We thank M.T. Mun ̃oz, A. Lo ́pez, T. Gil, and M. Bonete for technical support and Dr. Maria Calvo and Anna Bosch from the confocal microscopy unit at the Serveis Cientı ́fico-Te`cnics (Universitat de Barcelona) for their sup-port and advice on confocal techniques. We also thank Dr.K. Campbell for providing Dlx5/6Cre-IRES-EGFP trans-genic mice, Dr. Rudolf Grosschedl for Ebf1–/– mice, and Dr.Susan Winandy for Ikaros constructs. We are also very grateful to Robin Rycroft for the English language revisionS

Ikaros-1 couples cell cycle arrest of late striatal precursors with neurogenesis of enkephalinergic neurons

et al.During central nervous system development, several transcription factors regulate the differentiation of progenitor cells to postmitotic neurons. Here we describe a novel role for Ikaros-1 in the generation of late-born striatal neurons. Our results show that Ikaros-1 is expressed in the boundary of the striatal germinal zone (GZ)/mantle zone (MZ), where it induces cell cycle arrest of neural progenitors by up-regulation of the cyclin-dependent kinase inhibitor (CDKi) p21Cip1/Waf1. This effect is coupled with the neuronal differentiation of late precursors, which in turn is critical for the second wave of striatal neurogenesis that gives rise to matrix neurons. Consistently, Ikaros-/- mice had fewer striatal projecting neurons and, in particular, enkephalin (ENK)-positive neurons. In addition, overexpression of Ikaros-1 in primary striatal cultures increases the number of calbindin- and ENK-positive neurons. Our results also show that Ikaros-1 acts downstream of the Dlx family of transcription factors, insofar as its expression is lost in Dlx1/2 double knockout mice. However, we demonstrate that Ikaros-1 and Ebf-1 independently regulate the final determination of the two populations of striatal projection neurons of the matrix compartment, ENK- and substance P-positive neurons. In conclusion, our findings identify Ikaros-1 as a modulator of cell cycle exit of neural progenitors that gives rise to the neurogenesis of ENK-positive striatal neurons. © 2009 Wiley-Liss, Inc.Grant sponsor: Ministerio de Educacio´n y Ciencia; Grant number: BFU2005-04773/BMC(to O.M.); Grant number: SAF2006-05212 (to O.B.); Grant number: SAF2005-01335 (to J.A.); Grant number: SAF2006-04202 (to J.M.C.); Grant sponsor: Ministerio de Sanidad y Consumo [CIBERNED; to I.F., G.M., J.A., E.C.; Red de Terapia Celular (RETICS; to I.F. and J.M.C.)]; Grant sponsor: Fundació La Caixa (to O.M., J.A.); Grant sponsor: European Commission; Grant number: STREP 005139 (INTERDEVO; to O.M.) Grant sponsor: EURYI program (O.M.); Grant sponsor: CIRIT, Generalitat de Catalunya (to N.U.).Peer Reviewe

Ikaros-1 couples cell cycle arrest of late striatal precursors with neurogenesis of enkephalinergic neurons

During central nervous system development, several transcription factors regulate the differentiation of progenitor cells to postmitotic neurons. Here we describe a novel role for Ikaros-1 in the generation of late-born striatal neurons. Our results show that Ikaros-1 is expressed in the boundary of the striatal germinal zone (GZ)/mantle zone (MZ), where it induces cell cycle arrest of neural progenitors by up-regulation of the cyclin-dependent kinase inhibitor (CDKi) p21(Cip1/Waf1). This effect is coupled with the neuronal differentiation of late precursors, which in turn is critical for the second wave of striatal neurogenesis that gives rise to matrix neurons. Consistently, Ikaros(-/-) mice had fewer striatal projecting neurons and, in particular, enkephalin (ENK)-positive neurons. In addition, overexpression of Ikaros-1 in primary striatal cultures increases the number of calbindin- and ENK-positive neurons. Our results also show that Ikaros-1 acts downstream of the Dlx family of transcription factors, insofar as its expression is lost in Dlx1/2 double knockout mice. However, we demonstrate that Ikaros-1 and Ebf-1 independently regulate the final determination of the two populations of striatal projection neurons of the matrix compartment, ENK- and substance P-positive neurons. In conclusion, our findings identify Ikaros-1 as a modulator of cell cycle exit of neural progenitors that gives rise to the neurogenesis of ENK-positive striatal neurons.We thank M.T. Mun ̃oz, A. Lo ́pez, T. Gil, and M. Bonete for technical support and Dr. Maria Calvo and Anna Bosch from the confocal microscopy unit at the Serveis Cientı ́fico-Te`cnics (Universitat de Barcelona) for their sup-port and advice on confocal techniques. We also thank Dr.K. Campbell for providing Dlx5/6Cre-IRES-EGFP trans-genic mice, Dr. Rudolf Grosschedl for Ebf1–/– mice, and Dr.Susan Winandy for Ikaros constructs. We are also very grateful to Robin Rycroft for the English language revisionS