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First published online 7 July 2004
doi: 10.1242/dev.01204

Development 131, 3805-3819 (2004)
Published by The Company of Biologists 2004
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Sox2 deficiency causes neurodegeneration and impaired neurogenesis in the adult mouse brain

Anna L. M. Ferri1, Maurizio Cavallaro1, Daniela Braida2, Antonello Di Cristofano3, Annalisa Canta1, Annamaria Vezzani4, Sergio Ottolenghi1, Pier Paolo Pandolfi3, Mariaelvina Sala2, Silvia DeBiasi5 and Silvia K. Nicolis1,*

1 Department of Biotechnology and Biosciences, University of Milano-Bicocca, Piazza della Scienza 2, 20126 Milano, Italy
2 Department of Pharmacology, Chemotherapy and Medical Toxicology, University of Milano, via Vanvitelli 32, 20129 Milano, Italy
3 Cancer Biology and Genetics Program, and Department of Pathology, Memorial Sloan-Kettering Cancer Center, 1275 York Avenue, Box 110, New York, NY 10021, USA
4 Department of Neuroscience, `Mario Negri' Institute of Pharmacological Research, via Eritrea 62, 20157 Milano, Italy
5 Department of Biomolecular Sciences and Biotechnology, University of Milano, via Celoria 26, 20133 Milano, Italy

* Author for correspondence (e-mail: silvia.nicolis{at}unimib.it)

Accepted 2 April 2004

In many species, the Sox2 transcription factor is a marker of the nervous system from the beginning of its development, and we have previously shown that Sox2 is expressed in embryonic neural stem cells. It is also expressed in, and is essential for, totipotent inner cell mass stem cells and other multipotent cell lineages, and its ablation causes early embryonic lethality. To investigate the role of Sox2 in the nervous system, we generated different mouse mutant alleles: a null allele (Sox2ß-geo `knock-in'), and a regulatory mutant allele (Sox2{Delta}ENH), in which a neural cell-specific enhancer is deleted. Sox2 is expressed in embryonic early neural precursors of the ventricular zone and, in the adult, in ependyma (a descendant of the ventricular zone). It is also expressed in the vast majority of dividing precursors in the neurogenic regions, and in a small proportion of differentiated neurones, particularly in the thalamus, striatum and septum. Compound Sox2ß-geo/{Delta}ENH heterozygotes show important cerebral malformations, with parenchymal loss and ventricle enlargement, and L-dopa-rescuable circling behaviour and epilepsy. We observed striking abnormalities in neurones; degeneration and cytoplasmic protein aggregates, a feature common to diverse human neurodegenerative diseases, are observed in thalamus, striatum and septum. Furthermore, ependymal cells show ciliary loss and pathological lipid inclusions. Finally, precursor cell proliferation and the generation of new neurones in adult neurogenic regions are greatly decreased, and GFAP/nestin-positive hippocampal cells, which include the earliest neurogenic precursors, are strikingly diminished. These findings highlight a crucial and unexpected role for Sox2 in the maintenance of neurones in selected brain areas, and suggest a contribution of neural cell proliferative defects to the pathological phenotype.

Key words: Neural stem cells, Nervous system, Mouse, Sox2, Transcription factors, Neurogenesis, Hippocampal precursors, Neurodegeneration, Neuronal inclusions


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