Somatic sex reprogramming of adult ovaries to testes by FOXL2 ablation.

In mammals, the transcription factor SRY, encoded by the Y chromosome, is normally responsible for triggering the indifferent gonads to develop as testes rather than ovaries. However, testis differentiation can occur in its absence. Here we demonstrate in the mouse that a single factor, the forkhead transcriptional regulator FOXL2, is required to prevent transdifferentiation of an adult ovary to a testis. Inducible deletion of Foxl2 in adult ovarian follicles leads to immediate upregulation of testis-specific genes including the critical SRY target gene Sox9. Concordantly, reprogramming of granulosa and theca cell lineages into Sertoli-like and Leydig-like cell lineages occurs with testosterone levels comparable to those of normal XY male littermates. Our results show that maintenance of the ovarian phenotype is an active process throughout life. They might also have important medical implications for the understanding and treatment of some disorders of sexual development in children and premature menopause in women.

Loss of GLIS2 causes nephronophthisis in humans and mice by increased apoptosis and fibrosis.

Nephronophthisis (NPHP), an autosomal recessive kidney disease, is the most frequent genetic cause of end-stage renal failure in the first three decades of life. Positional cloning of the six known NPHP genes has linked its pathogenesis to primary cilia function. Here we identify mutation of GLIS2 as causing an NPHP-like phenotype in humans and mice, using positional cloning and mouse transgenics, respectively. Kidneys of Glis2 mutant mice show severe renal atrophy and fibrosis starting at 8 weeks of age. Differential gene expression studies on Glis2 mutant kidneys demonstrate that genes promoting epithelial-to-mesenchymal transition and fibrosis are upregulated in the absence of Glis2. Thus, we identify Glis2 as a transcription factor mutated in NPHP and demonstrate its essential role for the maintenance of renal tissue architecture through prevention of apoptosis and fibrosis.

A role for brain-specific homeobox factor Bsx in the control of hyperphagia and locomotory behavior.

Food intake and activity-induced thermogenesis are important components of energy balance regulation. The molecular mechanism underlying the coordination of food intake with locomotory behavior to maintain energy homeostasis is unclear. We report that the brain-specific homeobox transcription factor Bsx is required for locomotory behavior, hyperphagia, and expression of the hypothalamic neuropeptides Npy and Agrp, which regulate feeding behavior and body weight. Mice lacking Bsx exhibit reduced locomotor activity and lower expression of Npy and Agrp. They also exhibit attenuated physiological responses to fasting, including reduced increase of Npy/Agrp expression, lack of food-seeking behavior, and reduced rebound hyperphagia. Furthermore, Bsx gene disruption rescues the obese phenotype of leptin-deficient ob/ob mice by reducing their hyperphagia without increasing their locomotor activity. Thus, Bsx represents an essential factor for NPY/AgRP neuronal function and locomotory behavior in the control of energy balance.

Murine inner cell mass-derived lineages depend on Sall4 function.

Sall4 is a mammalian Spalt transcription factor expressed by cells of the early embryo and germ cells, an expression pattern similar to that of both Oct4 and Sox2, which play essential roles during early murine development. We show that the activity of Sall4 is cell-autonomously required for the development of the epiblast and primitive endoderm from the inner cell mass. Furthermore, no embryonic or extraembryonic endoderm stem cell lines could be established from Sall4-deficient blastocysts. In contrast, neither the development of the trophoblast lineage nor the ability to generate trophoblast cell lines from murine blastocysts was impaired in the absence of Sall4. These data establish Sall4 as an essential transcription factor required for the early development of inner cell mass-derived cell lineages.

The bHLH factor Olig3 coordinates the specification of dorsal neurons in the spinal cord.

Neurons of the dorsal horn integrate and relay sensory information and arise during development in the dorsal spinal cord, the alar plate. Class A and B neurons emerge in the dorsal and ventral alar plate, differ in their dependence on roof plate signals for specification, and settle in the deep and superficial dorsal horn, respectively. We show here that the basic helix-loop-helix (bHLH) gene Olig3 is expressed in progenitor cells that generate class A (dI1-dI3) neurons and that Olig3 is an important factor in the development of these neuronal cell types. In Olig3 mutant mice, the development of class A neurons is impaired; dI1 neurons are generated in reduced numbers, whereas dI2 and dI3 neurons are misspecified and assume the identity of class B neurons. Conversely, Olig3 represses the emergence of class B neurons in the chick spinal cord. We conclude that Olig3 expression distinguishes the two major classes of progenitors in the dorsal spinal cord and determines the distinct specification program of class A neurons.

The murine winged-helix transcription factor Foxl2 is required for granulosa cell differentiation and ovary maintenance.

Human Blepharophimosis/ptosis/epicanthus inversus syndrome (BPES) type I is an autosomal dominant disorder associated with premature ovarian failure (POF) caused by mutations in FOXL2, a winged-helix/forkhead domain transcription factor. Although it has been shown that FOXL2 is expressed in adult ovaries, its function during folliculogenesis is not known. Here, we show that the murine Foxl2 gene is essential for granulosa cell differentiation and ovary maintenance. In Foxl2(lacZ) homozygous mutant ovaries granulosa cells do not complete the squamous to cuboidal transition leading to the absence of secondary follicles and oocyte atresia. We further demonstrate that activin-betaA and anti-Mullerian inhibiting hormone expression is absent or strongly diminished in Foxl2(lacZ) homozygous mutant ovaries. Unexpectedly, two weeks after birth most if not all oocytes expressed Gdf9 in Foxl2(lacZ) homozygous mutant ovaries, indicating that nearly all primordial follicles have already initiated folliculogenesis at this stage. This activation, in the absence of functional granulosa cells, leads to oocyte atresia and progressive follicular depletion. In addition to providing a molecular mechanism for premature ovarian failure in BPES, these results suggest that granulosa cell function is not only crucial for oocyte growth but also to maintain follicular quiescence in vivo.