R-spondins are a recently characterized small family of growth factors. Here we show that human R-spondin1 (RSPO1) is the gene disrupted in a recessive syndrome characterized by XX sex reversal, palmoplantar hyperkeratosis and predisposition to squamous cell carcinoma of the skin. Our data show, for the first time, that disruption of a single gene can lead to complete female-to-male sex reversal in the absence of the testis-determining gene, SRY.

Mutations in SOX9 are associated with male-to-female sex reversal in humans. To analyze Sox9 function during sex determination, we ectopically expressed this gene in XX gonads. Here, we show that Sox9 is sufficient to induce testis formation in mice, indicating that it can substitute for the sex-determining gene Sry.

We conclude that although Sox9 is dispensable for hair induction, it directs differentiation of the ORS and is required for the formation of the hair stem cell compartment. Our genetic analysis places Sox9 in a molecular cascade downstream of sonic hedgehog and suggests that this gene is involved in basal cell carcinoma.

Liver zonation, the spatial separation of different metabolic pathways along the liver sinusoids, is fundamental for proper functioning of this organ, and its disruption can lead to the development of metabolic disorders such as hyperammonemia. Metabolic zonation involves the induction of β-catenin signaling around the central veins, but how this patterned activity is established and maintained is unclear. Here, we show that the signaling molecule Rspondin3 is specifically expressed within the endothelial compartment of the central vein. Conditional deletion of Rspo3 in mice disrupts activation of central fate, demonstrating its crucial role in determining and maintaining β-catenin-dependent zonation. Moreover, ectopic expression of Rspo1, a close family member of Rspo3, induces the expression of pericentral markers, demonstrating Rspondins to be sufficient to imprint a more central fate. Thus, Rspo3 is a key angiocrine factor that controls metabolic zonation of liver hepatocytes.

[1] In order to evaluate the activity of the Hawaiian hot spot, we calculate both the magma production rate, associated with volcanism, and the rate of swell formation, characteristic of the plume behavior. Both computations are made along the EmperorHawaii track. Depth anomaly is calculated by correcting the 2 0 bathymetry grid of Smith and Sandwell [1997] from thermal subsidence. A new filtering method is then used to separate the topography associated with volcanism and the swell surrounding the hot spot chain. The volume of magma includes the compensating root underlying the volcanoes, computed assuming either an Airy compensation (local) or a flexural root (regional) associated with the volcanic load. Next, the volume corresponding to the swell is calculated between the swell amplitude map and the zero value of the depth anomaly. Temporal variations of both volumes are then computed by the means of 1°Â 10°w indows translated along the hot spot track. Both volume fluxes are correlated through time and present (1) a general increase in amplitude for the last 30 Ma, indicating an increase in hot spot activity, and (2) short-wavelength oscillations with a 5 m.y. period, which may reflect the presence of solitary waves in the plume conduit. Contrary to the swell volume flux, the magma production rate estimation is not dependent on the subsidence model and is still valid for the older part of the chain. It is thus the most relevant parameter to describe the temporal variation of the Hawaiian hot spot behavior.

contributed equally to this workThe Wilms' tumor gene Wt1 is known for its important functions during genitourinary and mesothelial formation. Here we show that Wt1 is necessary for neuronal development in the vertebrate retina. Mouse embryos with targeted disruption of Wt1 exhibit remarkably thinner retinas than age-matched wildtype animals. A large fraction of retinal ganglion cells is lost by apoptosis, and the growth of optic nerve ®bers is severely disturbed. Strikingly, expression of the class IV POU-domain transcription factor Pou4f2 (formerly Brn-3b), which is critical for the survival of most retinal ganglion cells, is lost in Wt1 ±/± retinas. Forced expression of Wt1 in cultured cells causes an up-regulation of Pou4f2 mRNA. Moreover, the Wt1(±KTS) splice variant can activate a reporter construct carrying 5¢-regulatory sequences of the human POU4F2. The lack of Pou4f2 and the ocular defects in Wt1 ±/± embryos are rescued by transgenic expression of a 280 kb yeast arti®cial chromosome carrying the human WT1 gene. Taken together, our ®ndings demonstrate a continuous requirement for Wt1 in normal retina formation with a critical role in Pou4f2-dependent ganglion cell differentiation.

SUMMARY Adrenals and gonads share a common primordium (AGP), but the molecular events driving differentiation are poorly understood. Here we demonstrate that the Wilms’ tumor suppressor WT1 is a key factor defining AGP identity by inhibiting the steroidogenic differentiation process. Indeed, ectopic expression of WT1 precludes differentiation into adreno-cortical steroidogenic cells by locking them into a progenitor state. ChIP experiments identify Tcf21 and Gli1 as direct targets of WT1. Moreover, cell lineage tracing analyses identify a long-living progenitor population within the adrenal gland, characterized by the expression of WT1, GATA4, GLI1 and TCF21 that can generate steroidogenic cells in vivo. Strikingly, gonadectomy dramatically activates these WT1+ cells and leads to their differentiation into gonadal steroidogenic tissue. Thus our data describes a previously unknown mechanism of response to organ loss by recreating hormone-producing cells at a heterotopic site.

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