Charting the course of ovarian development in vertebrates.

The decision of the embryonic gonad to differentiate as either a testis or an ovary is a critical step in vertebrate development. The molecular basis of this decision has been the focus of much study, particularly over the past decade. Here we contrast the knowledge of early gonadal development and the switch to testis differentiation with the lack of molecular understanding of ovarian development at early stages.

Matching SOX: partner proteins and co-factors of the SOX family of transcriptional regulators.

SOX transcription factors perform a remarkable variety of important roles in vertebrate development, either activating or repressing specific target genes through interaction with different partner proteins. Surprisingly, these interactions are often mediated by the conserved, DNA-binding HMG domain, raising questions as to how each factor's specificity is generated. We propose a model whereby non-HMG domains may influence partner protein selection and/or binding stability.

Expression-based strategies for discovery of genes involved in testis and ovary development.

In recent years, strategies for gene identification based on differential gene expression have become increasingly popular, due in part to the development of microarray technology. These strategies are particularly well suited to the identification of genes involved in sex determination and gonadal development, which unlike the development of other organ systems, proceeds along two very different alternative courses, depending on the sex of the embryo. We have used a high-throughput, array-based expression screen to identify several genes expressed sex-specifically in developing mouse gonads.

SOX18 and the transcriptional regulation of blood vessel development.

SOX18 is a transcription factor that is transiently expressed in nascent endothelial cells during embryonic development and adult neovascularization. This protein belongs to the SOX family of transcription factors, which are proving to be some of the key regulators of cell-type specification in the vertebrate embryo. Natural mutations in the Sox18 gene have been shown to result in cardiovascular dysfunction, in some cases leading to death.

New clues to the puzzle of mammalian sex determination.

WT1 and SOX9 are transcription factors with critical roles in mammalian sex determination and gonadal development. Recent studies in vivo clarify the roles of two alternative splice isoforms of WT1, and demonstrate that SOX9 can induce male sex determination.

Searching for missing pieces of the sex-determination puzzle.

Little is known of the mechanisms whereby the mammalian indifferent gonad develops into a testis or ovary. In XY individuals, Sry, the mammalian testis-determining gene, is expressed in the pre-Sertoli cells, which then differentiate into Sertoli cells. Other cell types, which include the germ cells, the steroidogenic cells and the connective tissue cells, must then be instructed to develop in a male-specific manner.

Regulation of male sexual development by Sry and Sox9.

Sry, a gene from the Y chromosome, is known to initiate testis formation and subsequent male differentiation in mammals. A related gene, Sox9, also plays a critical role in testis determination, possibly in all vertebrates. A number of models have been presented regarding the molecular modes of action of these two genes.

SOX18 directly interacts with MEF2C in endothelial cells.

Recently, we demonstrated that mutations in the Sry-related HMG box gene Sox18 underlie vascular and hair follicle defects in the mouse allelic mutants ragged (Ra) and RaJ. Ra mice display numerous anomalies in the homozygote including, oedema, peritoneal secretions, and are almost completely naked. Sox18 and the MADS box transcription factor, Mef2C, are expressed in developing endothelial cells.

Transcriptional suppression of Sox9 expression in chondrocytes by retinoic acid.

SOX9 is a transcription factor that is expressed in chondrocytes and regulates expression of chondrocyte phenotype related genes. Expression of these genes is known to be suppressed by retinoic acid (RA). We, therefore, examined whether the Sox9 gene expression is regulated by RA in chondrocytes.

Sox18 is transiently expressed during angiogenesis in granulation tissue of skin wounds with an identical expression pattern to Flk-1 mRNA.

Sox18 encodes a member of the Sry-related high mobility group box (SOX) family of developmental transcription factors. Examination of Sox18 expression during embryogenesis has shown that Sox18 is expressed transiently in endothelial cells of developing blood vessels, and mutations in Sox18 have been found to underlie the mouse vascular and hair follicle mutant ragged. In this study we have examined the expression of Sox18 in angiogenesis during wound healing.

Gonad development: signals for sex.

The formation of testes or ovaries in the mammalian embryo is critical in determining sexual identity and the ability to reproduce. Recent studies have begun to illuminate the cellular signalling events required for development of functional testes.

Sox18 expression in blood vessels and feather buds during chicken embryogenesis.

Sox18 encodes a transcription factor known to be important for the development of blood vessels and hair follicles in mice. In order to study the functional conservation of this gene through evolution, we have isolated and characterized Sox18 in chickens. cSox18 shows a high degree of sequence homology to both the mouse and human orthologues, particularly in the high mobility group DNA-binding domain and to a lesser extent in the transcriptional activation domain.

In situ hybridization to mRNA: from black art to guiding light.

In situ hybridization to mRNA in embryo sections or wholemount embryos is one of the most powerful analytical tools available to the molecular developmental biologist. For many workers, this procedure provides the first insights into the function of newly isolated genes, allowing the formulation of hypotheses and setting the course for further research. This paper presents a personal historical perspective of the development of in situ hybridization, looks at the theory and practice of the technique, summarizes the current state of the art, and speculates on possible directions for the future as a tool in functional genomics.

Spatially dynamic expression of Sry in mouse genital ridges.

We have studied the spatial dynamics of Sry transcription in the genital ridges of mouse embryos. We find that Sry is expressed in a dynamic wave that emanates from the central and/or anterior regions, extends subsequently to both poles, and ends in the caudal pole. This dynamism may explain the relative positioning of ovarian and testicular tissue seen in ovotestes in mice.

Dexamethasone enhances SOX9 expression in chondrocytes.

SOX9 is a transcription factor that activates type II procollagen (Col2a1) gene expression during chondrocyte differentiation. Glucocorticoids are also known to promote chondrocyte differentiation via unknown molecular mechanisms. We therefore investigated the effects of a synthetic glucocorticoid, dexamethasone (DEX), on Sox9 gene expression in chondrocytes prepared from rib cartilage of newborn mice.

Transcriptional modulation of mouse mu-opioid receptor distal promoter activity by Sox18.

Previously, we reported the presence of dual promoters, referred to as distal (DP) and proximal, with a negative regulatory element between them in the mouse mu-opioid receptor (mor) gene. Here we have identified a positive regulatory element influencing mor DP transcription, which contains multiple consensus binding motifs for Sox factors (sex-determining Sry-like high mobility group box-containing genes). In gel supershift assays, the Sox family member Sox18 bound directly to the multiple Sox consensus binding motifs of the mor DP enhancer.

Sry, Sox9 and mammalian sex determination.

Sry is the Y-chromosomal gene that acts as a trigger for male development in mammalian embryos. This gene encodes a high mobility group (HMG) box transcription factor that is known to bind to specific target sequences in DNA and to cause a bend in the chromatin. DNA bending appears to be part of the mechanism by which Sry influences transcription of genes downstream in a cascade of gene regulation leading to maleness, but the factors that cooperate with, and the direct targets of, Sry remain to be identified.

Cloning and functional analysis of the Sry-related HMG box gene, Sox18.

The Sox gene family (Sry like HMG box gene) is characterised by a conserved DNA sequence encoding a domain of approximately 80 amino acids which is responsible for sequence specific DNA binding. We initially published the identification and partial cDNA sequence of murine Sox18, a new member of this gene family, isolated from a cardiac cDNA library. This sequence allowed us to classify Sox18 into the F sub-group of Sox proteins, along with Sox7 and Sox17.

SOX9 enhances aggrecan gene promoter/enhancer activity and is up-regulated by retinoic acid in a cartilage-derived cell line, TC6.

SOX9 is a transcription factor that plays a key role in chondrogenesis. Aggrecan is one of the major structural components in cartilage; however, the molecular mechanism of aggrecan gene regulation has not yet been fully elucidated. TC6 is a clonal chondrocytic cell line derived from articular cartilage.

Mice null for sox18 are viable and display a mild coat defect.

We have previously shown that Sox18 is expressed in developing vascular endothelium and hair follicles during mouse embryogenesis and that point mutations in Sox18 are the underlying cause of cardiovascular and hair follicle defects in ragged (Ra) mice. Here we describe the analysis of Sox18(-/-) mice produced by gene targeting. Despite the profound defects seen in Ra mice, Sox18(-/-) mice have no obvious cardiovascular defects and only a mild coat defect with a reduced proportion of zigzag hairs.

Characterisation of Crim1 expression in the developing mouse urogenital tract reveals a sexually dimorphic gonadal expression pattern.

The Crim1 gene encodes a putative transmembrane protein with an IGF-binding protein motif and multiple chordin-like cysteine-rich repeats. In chordin, such repeats are responsible for its dorsalising activity and for binding to bone morphogenic proteins (BMPs). Crim1 displays a dynamic expression pattern in a variety of developing organs, including the CNS and the lens.

Phylogeny of the SOX family of developmental transcription factors based on sequence and structural indicators.

Members of the SOX family of transcription factors are found throughout the animal kingdom, are characterized by the presence of a DNA-binding HMG domain, and are involved in a diverse range of developmental processes. Previous attempts to group SOX genes and deduce their structural, functional, and evolutionary relationships have relied largely on complete or partial HMG box sequence of a limited number of genes. In this study, we have used complete HMG domain sequence, full-length protein structure, and gene organization data to study the pattern of evolution within the family.