Sry and sex determination: how lazy can it be?
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Amino Acid Sequence↗
Biomedical subjects
Robin Lovell-Badge
Publications and source records attributed to Robin Lovell-Badge.
Dax1 expression is dependent on steroidogenic factor 1 in the developing gonad.
The nuclear hormone receptor DAX1 has been implicated in mammalian gonad development and sex determination. The expression of the gene in the gonad follows a dynamic pattern in time and place in the embryo and the adult. We have undertaken the first in vivo study of the regulation of Dax1 expression. Using a transgenic mouse approach we have identified a novel 500-bp region 4 kb upstream of the mouse Dax1 start codon that is essential for LacZ reporter gene expression in the embryonic gonad. Within this region, a highly conserved steroidogenic factor 1 (SF1) consensus-binding site is necessary to direct LacZ expression to the embryonic gonad implicating SF1 in the regulation of Dax1 in the developing gonad. Consistent with this, Dax1 is expressed at much reduced levels in gonads of embryos that are deficient in SF1. In addition, our results show that SF1 consensus-binding sites close to the start of Dax1 transcription are important in regulating levels of expression in the developing gonad. These studies have identified the critical in vivo regulatory region for expression of Dax1 in the early gonad and provide novel information on how a specific enhancer element acts in different cell types at different stages of development.
Animals↗
Sex-determining genes in mice: building pathways.
Sry is active in the mouse for a very brief period in somatic cells of the genital ridge to initiate Sertoli cell differentiation. SRY protein must act within the context of other gene products required for gonadal development and must itself act on one or more target genes that will ensure the further differentiation and maintenance of Sertoli cells. Over the last few years several genes have been found that have important roles in gonadal development and sex determination. These include genes encoding transcription factors such as Lhx9, Wt1, Sf1, Dax1, Gata4, Dmrt1 and Sox9, and some involved in cell cell signalling, including Amh, Wnt4 and Dhh. While more await discovery, it is now possible to start putting some of the known genes into pathways or networks. Sox9 probably occupies a critical role in mammals for both the initiation and maintenance of Sertoli cell differentiation. Data will be presented that are consistent with SRY acting directly on Sox9 to ensure its up-regulation. SF1 is also central to gonadal differentiation. Our results imply that it contributes to transcriptional activation of several relevant genes, not just those required for male development, including Sox9 and Amh, but also those that can have an antagonistic effect on Sertoli cell differentiation, such as Dax1. Progress in establishing other regulatory interactions will also be discussed.
Animals↗