Sox2deficiency causes neurodegeneration and impaired neurogenesis in the adult mouse brain

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.

Transcription factor protein expression patterns by neural or neuronal progenitor cells of adult monkey subventricular zone

“…We observed certain similarities between our results in monkeys and studies using nonprimate models with respect to transcription factor expression by adult SVZa progenitors. In particular, Emx2 and Sox2,3 were expressed by actively dividing sustained progenitors in monkey SVZa consistent with their previously reported expression in early multipotent progenitor/stem cells (Galli et al, 2002;Bylund et al, 2003;Graham et al, 2003;Ferri et al, 2004;Komitova and Eriksson, 2004), while Sox1 (but not Sox2,3) protein was predominantly localized in monkey neuronal progenitors consistent with its previously reported activity inducing neuronal commitment (Kan et al, 2004). At the same time, we noticed the following discrepancies between our results in monkeys and studies using nonprimate animal models.…”

“…This concept was supported by data in rodents showing that transcriptional regulators of embryonic precursors were also expressed by adult SVZa progenitors: Pax6 and Olig2 (Hack et al, 2004), Emx2 (Galli et al, 2002), Dlx2 (Doetsch et al, 2002), and Sox2 (Ferri et al, 2004;Komitova and Eriksson, 2004). We first report expression of developmentally-regulated transcription factors at protein level by SVZa progenitor cells of adult primate brain.…”

“…Expression of several of these developmental signals has been shown in adult rodent SVZa precursors, including paired-box (Pax) 6 (Heins et al, 2002;Hack et al, 2004), empty spiracles-homeobox (Emx) 2 (Galli et al, 2002), distalless-homeobox (Dlx) 2 (Doetsch et al, 2002), sex determining region Y-box (Sox) 2 (Ferri et al, 2004;Komitova and Eriksson, 2004), and oligodendrocyte lineage gene (Olig) 2 (Hack et al, 2004). At present, however, little is known of transcription factor expression by progenitor cells in adult primate SVZa.…”

Complementary expression pattern of Zfhx1 genes Sip1 and δEF1 in the mouse embryo and their genetic interaction revealed by compound mutants

“…4E), a gene encoding a transcription factor involved in neural plate development (Collignon et al, 1996;Wood and Episkopou, 1999;Ferri et al, 2004). In Sip1Ϫ/Ϫ embryos, Sox2 expression was significantly decreased throughout the neural plate, as briefly described previously (Fig.…”

Sox2 is dispensable for primary melanoma and metastasis formation

“…It controls pluripotency in embryonic stem cells and is one of the four originally described factors required for reprogramming of differentiated cells into induced pluripotent stem cells 3,4 . Sox2 has been extensively studied in the central nervous system, where it regulates maintenance of stem and progenitor cells [5][6][7][8] . Likewise, in adult mouse tissue, Sox2 marks epithelial stem cells in various tissues of endodermal and ectodermal origin and is required for their homeostasis 9 .…”