Cloning and mapping of platypus SOX2 and SOX14: insights into SOX group B evolution

Group B SOX genes, the closest relatives to the sex-determining gene SRY, are thought to have evolved from a single ancestral SOX B by a series of duplications and translocations. The two SOX B genes SOX2 and SOX14 co-localize to chromosome 3q in humans. SOX2 and SOX14 homologues were cloned and characterized in the platypus, a monotreme mammal distantly related to man. The two genes were found to co-localize to chromosome 1q in this species. Proximity of the two related genes has therefore been conserved for 170 Myr, since humans and platypus diverged. The sequence similarity and conserved synteny of these group B genes provide clues to their origin. A simple model of SOX group B gene evolution is proposed.     

Shuttling of SOX proteins

The control of access of SOX proteins to their nuclear target genes is a powerful strategy to activate or repress complex genetic programs. The sub-cellular targeting sequences of SOX proteins are concentrated within the DNA binding motif, the HMG (for high mobility group) domain. Each SOX protein displays two different nuclear localization signals located at the N-terminal and C-terminal part of their highly conserved DNA binding domain. The N-terminal nuclear localization signal binds calmodulin and is potentially regulated by intracellular calcium signalling, while the C-terminal nuclear localization signal, which binds importin-β, responds to other signalling pathways such as cyclic AMP/protein kinase A. Mutations inducing developmental disorders like sex reversal have been reported in both NLSs of SRY, interfering with its nuclear localization and suggesting that both functional nuclear localization signal are required for its nuclear activity. A nuclear export signal is also present in the HMG box of SOX proteins. Group E SOX proteins harbour a perfect consensus nuclear export signal sequence in contrast to all other SOX proteins, which display only imperfect ones. However, observations made during mouse embryonic development suggest that non-group E SOX proteins could also be regulated by a nuclear export mechanism. The presence of nuclear localization and nuclear export signal sequences confers nucleocytoplasmic shuttling properties to SOX proteins, and suggests that cellular events regulated by SOX proteins are highly dynamic.     

SOX基因家族的研究现状

ＳＯＸ基因家族是一个新发现的基因家族,其主要特征是具有一个保守基序———ＨＭＧ -ｂｏｘ,可以和ＤＮＡ进行序列特异性的结合。该家族的第一个成员是哺乳动物的性别决定基因ＳＲＹ／Ｓｒｙ。由于ＳＯＸ基因在胚胎发育及性别分化过程中可能起着重要的作用,对其研究进展十分迅速。本文根据现有资料总结了有关方面的研究成果。１ＳＯＸ基因的发现人类中存在一些性反转患者 (ＸＸ男性或ＸＹ女性 ),其性别表型与其性染色体组成不一致。详尽分析其染色体结构,发现前者大多获得了一段Ｙ片段;后者往往失去了一段Ｙ染色体片段,由于不同患者…     

Mechanism of Regulatory Target Selection by the SOX High-Mobility-Group Domain Proteins as Revealed by Comparison of SOX1/2/3 and SOX9

SOX proteins bind similar DNA motifs through their high-mobility-group (HMG) domains, but their action is highly specific with respect to target genes and cell type. We investigated the mechanism of target selection by comparing SOX1/2/3, which activate δ-crystallin minimal enhancer DC5, with SOX9, which activates Col2a1 minimal enhancer COL2C2. These enhancers depend on both the SOX binding site and the binding site of a putative partner factor. The DC5 site was equally bound and bent by the HMG domains of SOX1/2 and SOX9. The activation domains of these SOX proteins mapped at the distal portions of the C-terminal domains were not cell specific and were independent of the partner factor. Chimeric proteins produced between SOX1 and SOX9 showed that to activate the DC5 enhancer, the C-terminal domain must be that of SOX1, although the HMG domains were replaceable. The SOX2-VP16 fusion protein, in which the activation domain of SOX2 was replaced by that of VP16, activated the DC5 enhancer still in a partner factor-dependent manner. The results argue that the proximal portion of the C-terminal domain of SOX1/2 specifically interacts with the partner factor, and this interaction determines the specificity of the SOX1/2 action. Essentially the same results were obtained in the converse experiments in which COL2C2 activation by SOX9 was analyzed, except that specificity of SOX9-partner factor interaction also involved the SOX9 HMG domain. The highly selective SOX-partner factor interactions presumably stabilize the DNA binding of the SOX proteins and provide the mechanism for regulatory target selection.     

Mapping platypus SOX genes; autosomal location of SOX9 excludes it from sex determining role

In the absence of an SRY orthologue the platypus sex determining gene is unknown, so genes in the human testis determining pathway are of particular interest as candidates. SOX9 is an attractive choice because SOX9 deletions cause male-to-female sex reversal in humans and mice, and SOX9 duplications cause female-to-male sex reversal. We have localized platypus SOX9, as well as the related SOX10, to platypus chromosomes 15 and 10, respectively, the first assignments to these platypus chromosomes, and the first comparative mapping markers from human chromosomes 17 and 22. The autosomal localization of platypus SOX9 in this study contradicts the hypothesis that SOX9 acts as the sex determining switch in platypus.     

SOX8 expression during chick embryogenesis

We have isolated the SOX8 gene from the chicken embryo. This gene shows a high degree of sequence homology to SOX9 and SOX10. Detailed analysis of SOX8 expression by whole-mount in situ shows a dynamic and restricted expression pattern during chick development. SOX8 is expressed in the somitic derivative, the dermomyotome, the developing heart, pancreas, enteric neurone system, limb and the neural tube. This is the first detailed expression analysis of SOX8 in any species     

SOX9基因与性别决定的关系

1 .性别决定简介[1～ 5 ]哺乳动物包括人类的性别决定问题一直是科学史上的一个难解之谜。科学家们经过异常艰苦的研究才逐步揭开性别决定的神秘面纱。位于男性Ｙ染色体上的ＳＲＹ(ｓｅｘｄｅ ｔｅｒｍｉｎｇｒｅｇｉｏｎｏｆＹｃｈｒｏｍｏｓｏｍｅ)基因是当前被确定的睾丸决定因子 (ＴＤＦ)的主要侯选基因 ,它是哺乳动物中睾丸发育的主要诱导者。ＳＲＹ基因编码的蛋白质含有与ＤＮＡ结合的模体 ,称为ＨＭＧ盒 (与高速泳动类蛋白质相关的一种模体 )。ＨＭＧ盒存在于很多转录因子中。ＳＲＹ蛋白的ＨＭＧ盒与特定的ＤＮＡ序列结合 ,表明它在…