Sox2 deficiency causes neurodegeneration and impaired neurogenesis in the adult mouse brain

Anna L M Ferri, Maurizio Cavallaro, Daniela Braida, Antonio Di Cristofano, Annalisa Canta, Annamaria Vezzani, Sergio Ottolenghi, Pier Paolo Pandolfi, Mariaelvina Sala, Silvia DeBiasi, Silvia K. Nicolis

Research output: Contribution to journalArticle

452 Citations (Scopus)

Abstract

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 (Sox2β-geo 'knock-in'), and a regulatory mutant allele (Sox2ΔENH), 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 Sox2β-geo/ΔENH 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.

Original languageEnglish (US)
Pages (from-to)3805-3819
Number of pages15
JournalDevelopment
Volume131
Issue number15
DOIs
StatePublished - Aug 2004
Externally publishedYes

Fingerprint

Neurogenesis
Brain
Neurons
Alleles
Thalamus
Nervous System
Ependyma
Multipotent Stem Cells
Nestin
Neural Stem Cells
Levodopa
Cell Lineage
Embryonic Stem Cells
Heterozygote
Neurodegenerative Diseases
Epilepsy
Transcription Factors
Maintenance
Cell Proliferation
Phenotype

Keywords

  • Hippocampal precursors
  • Mouse
  • Nervous system
  • Neural stem cells
  • Neurodegeneration
  • Neurogenesis
  • Neuronal inclusions
  • Sox2
  • Transcription factors

ASJC Scopus subject areas

  • Anatomy
  • Cell Biology

Cite this

Ferri, A. L. M., Cavallaro, M., Braida, D., Di Cristofano, A., Canta, A., Vezzani, A., ... Nicolis, S. K. (2004). Sox2 deficiency causes neurodegeneration and impaired neurogenesis in the adult mouse brain. Development, 131(15), 3805-3819. https://doi.org/10.1242/dev.01204

Sox2 deficiency causes neurodegeneration and impaired neurogenesis in the adult mouse brain. / Ferri, Anna L M; Cavallaro, Maurizio; Braida, Daniela; Di Cristofano, Antonio; Canta, Annalisa; Vezzani, Annamaria; Ottolenghi, Sergio; Pandolfi, Pier Paolo; Sala, Mariaelvina; DeBiasi, Silvia; Nicolis, Silvia K.

In: Development, Vol. 131, No. 15, 08.2004, p. 3805-3819.

Research output: Contribution to journalArticle

Ferri, ALM, Cavallaro, M, Braida, D, Di Cristofano, A, Canta, A, Vezzani, A, Ottolenghi, S, Pandolfi, PP, Sala, M, DeBiasi, S & Nicolis, SK 2004, 'Sox2 deficiency causes neurodegeneration and impaired neurogenesis in the adult mouse brain', Development, vol. 131, no. 15, pp. 3805-3819. https://doi.org/10.1242/dev.01204
Ferri, Anna L M ; Cavallaro, Maurizio ; Braida, Daniela ; Di Cristofano, Antonio ; Canta, Annalisa ; Vezzani, Annamaria ; Ottolenghi, Sergio ; Pandolfi, Pier Paolo ; Sala, Mariaelvina ; DeBiasi, Silvia ; Nicolis, Silvia K. / Sox2 deficiency causes neurodegeneration and impaired neurogenesis in the adult mouse brain. In: Development. 2004 ; Vol. 131, No. 15. pp. 3805-3819.
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AU - Canta, Annalisa

AU - Vezzani, Annamaria

AU - Ottolenghi, Sergio

AU - Pandolfi, Pier Paolo

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AU - Nicolis, Silvia K.

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