A comparison of the properties of Sox-3 with Sry and two related genes, Sox-1 and Sox-2

The Sox gene family consists of a large number of embryonically expressed genes related via the possession of a 79-amino-acid DNA-binding domain known as the HMG box, Partial clones for the first three Sox genes (a1-a3) were isolated by homology to the HMG box of the testis-determining gene Sry and are now termed Sox-1, Sox-2 and Sox-3, Sox-3 is highly conserved amongst mammalian species and is located on the X chromosome, This has led to the proposal that Sry evolved from Sox-3, We present the cloning and sequencing of Sox-1, Sox-2 and Sox-3 from the mouse and show that Sox-3 is most closely related to Sry. We also confirm that mouse Sox-3 is located on the X chromosome between Hprt and Dmd. Analysis of the distribution of Sox-3 RNA shows that its main site of expression is in the developing central nervous system, suggesting a role for Sox-3 in neural development, Moreover, we demonstrate that Sox-3, as well as Sox-1 and Sox-2, are expressed in the urogenital ridge and that their protein products are able to bind the same DNA sequence motif as Sry in vitro, but with different affinities, These observations prompt discussion of an evolutionary link between the genes and support the model that Sry has evolved from Sox-3, However our findings imply that if this is true, then Sry has undergone concomitant changes resulting in loss of CNS expression and altered DNA-binding properties

Disruption of Murine Hexa Gene Leads To Enzymatic Deficiency and To Neuronal Lysosomal Storage, Similar To That Observed in Tay-sachs-disease

Tay-Sachs disease is an autosomal recessive lysosomal storage disease caused by beta-hexosaminidase A deficiency and leads to death in early childhood. The disease results from mutations in the HEXA gene, which codes for the alpha chain of beta-hexosaminidase. The catastrophic neurodegenerative progression of the disease is thought to be a consequence of massive neuronal accumulation of G(M2) ganglioside and related glycolipids in the brain and nervous system of the patients. Fuller understanding of the pathogenesis and the development of therapeutic procedures have both suffered from the lack of an animal model. We have used gene targeting in embryonic stent (ES) cells to disrupt the mouse Hexa gene. Mice homozygous for the disrupted allele mimic several biochemical and histological features of human Tay-Sachs disease. Hexa -/- mice displayed a total deficiency of beta-hexosaminidase A activity, and membranous cytoplasmic inclusions typical of G(M2) gangliosidoses were found in the cytoplasm of their neurons. However, while the number of storage neurons increased with age, it remained low compared with that found in human, and no apparent motor or behavioral disorders could be observed. This suggests that the presence of beta-hexosaminidase A is not an absolute requirement of ganglioside degradation in mice. These mice should help us to understand several aspects of the disease as well as the physiological functions of hexosaminidase in mice, They should also provide a valuable animal model in which to test new forms of therapy, and in particular gene delivery into the central nervous system