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Published 19 August 2002. doi:10.1083/jcb.200202024
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© The Rockefeller University Press, 0021-9525/2002/8/731 $5.00
The Journal of Cell Biology, Volume 158, Number 4, August 19, 2002 731-740

Article

 Ren : a novel, developmentally regulated gene that promotes neural cell differentiation



Rita Gallo1, Francesca Zazzeroni1, Edoardo Alesse1, Claudia Mincione2, Ugo Borello3,6, Pasquale Buanne1, Roberta D'Eugenio1, Andrew R. Mackay1, Beatrice Argenti2, Roberto Gradini2, Matteo A. Russo2, Marella Maroder2, Giulio Cossu3,6, Luigi Frati2,5, Isabella Screpanti2,4 and Alberto Gulino2

1 Department of Experimental Medicine, University of L'Aquila, 67100 L'Aquila, Italy
2 Department of Experimental Medicine and Pathology, Pasteur Institute, University La Sapienza, 00161 Rome, Italy
3 Department of Histology and Embryology, Pasteur Institute, University La Sapienza, 00161 Rome, Italy
4 Cenci-Bolognetti Foundation, Pasteur Institute, University La Sapienza, 00161 Rome, Italy
5 Neuromed Institute, 86077 Pozzilli, Italy
6 Stem Cell Research Institute, Dibit, H. San Raffaele, 20132 Milan, Italy

Address correspondence to Alberto Gulino, Dept. of Experimental Medicine and Pathology, University La Sapienza, 324, viale Regina Elena, 00161 Rome, Italy. Tel.: 39-06-446-4021. Fax: 39-06-446-1974. E-mail: alberto.gulino{at}uniroma1.it

Expansion and fate choice of pluripotent stem cells along the neuroectodermal lineage is regulated by a number of signals, including EGF, retinoic acid, and NGF, which also control the proliferation and differentiation of central nervous system (CNS) and peripheral nervous system (PNS) neural progenitor cells. We report here the identification of a novel gene, REN, upregulated by neurogenic signals (retinoic acid, EGF, and NGF) in pluripotent embryonal stem (ES) cells and neural progenitor cell lines in association with neurotypic differentiation. Consistent with a role in neural promotion, REN overexpression induced neuronal differentiation as well as growth arrest and p27Kip1 expression in CNS and PNS neural progenitor cell lines, and its inhibition impaired retinoic acid induction of neurogenin-1 and NeuroD expression. REN expression is developmentally regulated, initially detected in the neural fold epithelium of the mouse embryo during gastrulation, and subsequently throughout the ventral neural tube, the outer layer of the ventricular encephalic neuroepithelium and in neural crest derivatives including dorsal root ganglia. We propose that REN represents a novel component of the neurogenic signaling cascade induced by retinoic acid, EGF, and NGF, and is both a marker and a regulator of neuronal differentiation.

Key Words: EGF; NGF; retinoic acid; neurogenic bHLH; neural cell


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