09-P087 FGF signaling is required for the specification of GnRH neurons

Abstract

mutation Vcc (Vacterl/caudal regression/Currarino syndromelike) exhibit a pleiotropic phenotype including abnormalities of cardiac, skeletal and limb development, in addition to renal agenesis. Here we report abnormalities of gonad development in homozygous mutants. From early stages, Vcc/Vcc embryos contain gonads longer than controls and by 13.5 dpc this increased length is evidenced by an increase in the number of testis cords.The gene mutated in Vcc, Pcsk5, encodes a proprotein convertase that is thought to co-ordinately regulate the expression of several paralogous Hox genes. Utilising a variety of approaches, we are investigating the possibility that abnormal HOX-dependent patterning of the urogenital ridge in Vcc/Vcc embryos expands the gonadal field, resulting in the striking lengthening of the mutant gonads. Studies of this mutation may shed light on the cellular processes underlying gonad formation and subsequent testis cord formation in males, and their genetic regulation.Adult stem cells are indispensable for tissue homeostasis. Due to their life-long importance, these cells must be protected from metabolic and genetic damage. Most adult stem cells are thought to enter a quiescent state, which is defined as a reversible cell cycle arrest, but rather uncharacterized regarding molecular mechanisms.We previously demonstrated that the expression of various key molecules, including several housekeeping genes, is down-regulated in melanocyte stem cells (MSCs). These results led us to test whether transcription of mRNA is globally suppressed in MSCs.The different stages of mRNA transcription are regulated by phosphorylation of the C-terminal domain (CTD) of RNA polymerase II (RNApII). We found, using specific anti-phospho antibodies, that MSCs exhibit a significant down-regulation of mRNA transcription elongation as compared to differentiated melanocytes, while the initiated form of RNApII was detected in both populations. In line with this, expression of the CTD kinase CDK9 was lower in MSC compared to differentiated cells. Inhibition of CDK9 activity in melanocyte precursors led to decreased levels of CTD phosphorylation and improved survival upon blockage of c-Kit signaling, a feature characteristic for MSC. Interestingly, also other adult stem cells, including keratinocyte, muscle, spermatogonia and haematopoietic stem cells, showed a similar down-regulation of mRNA transcription elongation, while surrounding somatic cells were always positive. We conclude that absence of productive mRNA transcription is a characteristic of adult stem cells. Down-regulation of mRNA transcription might lead to decreased rates of metabolism and protection from cellular and genetic damage. Gonadotropin-releasing hormone (GnRH) is an essential regulator of postnatal sexual maturation and fertility. It is expressed in a discrete population of neurosecretory cells located throughout the basal hypothalamus and is released into the hypothalamo-hypophyseal portal vessels. The secreted GnRH is transported to the anterior pituitary...