La glande surrénale est un organe endocrinien d’une importance vitale de par son rôle dans le maintien de l’homéostasie corporelle. Pour assurer cette fonction, le cortex surrénalien est divisé en différentes zones qui produisent des hormones spécifiques. Les mécanismes de la mise en place de cette zonation au niveau embryonnaire ainsi que de son maintien tout au long de vie sont encore inconnus de nos jours. Les gènes Rspo1 et 3 sont exprimés de manière très spécifique au niveau de la capsule mais ils codent pour des protéines secrétées qui agissent sur les cellules adjacentes de la zone glomérulée afin d’induire l’activation de la voie canonique Wnt/β-caténine. La délétion du gène Rspo3 pendant le développement embryonnaire entraine un défaut d’activation des voies Shh et Wnt/β-caténine et donc en conséquence un défaut de la mise en place de la zonation. Sa fonction reste également essentielle au cours de la vie adulte puisqu’elle assure à la fois le maintien de l’homéostasie tissulaire et de la zone glomérulée. L’absence du gène Rspo1, n’affecte pas le développement ni la zonation ou l’homéostasie de la glande surrénale. Par contre, si on l’exprime de façon ectopique dans tous le cortex surrénalien, entrainant une activation anormale de la voie Wnt/β-caténine dans cette zone, on peut observer une hyperplasie des glandes surrénales. A partir de 1 an d’âge, cette hyperplasie surrénalienne entraine une formation de tumeurs. Ce travail démontre donc que la capsule par le biais du gène Rspondin 3 agit comme un centre de signalisation capable de contrôler à la fois l’homéostasie par le remplacement des cellules endommagés et le maintien de la zonation de la glande surrénale / The adrenal gland is an endocrine organ of vital importance because of its role in the maintenance of body homeostasis. To ensure this function, the adrenal cortex is divided into different areas that produce specific hormones. The mechanisms of the establishment of this zonation at the embryonic level as well as its maintenance throughout life are still unknown today. The Rspo1 and 3 genes are expressed very specifically at the capsule level but they encode secreted proteins that act on the adjacent cells of the zona glomerulosa in order to induce the activation of the Wnt / β-catenin canonical pathway. The deletion of the Rspo3 gene during embryonic development leads to a lack of activation of the Shh and Wnt / β-catenin pathways and hence a lack of zonation. Its function is also essential during adult life since it ensures both the maintenance of tissue homeostasis and the glomerular zone. The absence of the Rspo1 gene does not affect development, zonation or homeostasis of the adrenal gland. On the other hand, its ectopical expression in all the adrenal cortex leads to an abnormal activation of the Wnt / β-catenin pathway in this area and thus to an hyperplasia of the adrenal glands. From 1 year of age, this adrenal hyperplasia leads to the formation of tumors. This work demonstrates that the capsule through the Rspondin 3 gene acts as a signaling center capable of controlling both homeostasis by replacing damaged cells and maintaining the zonation of the adrenal gland

The cWnt activator, Rspondin-1 (Rspo1), has been identified as a regulator of β-cell growth and function, although its role in pathophysiological conditions such as streptozotocin (STZ)-induced diabetes is unknown. Hence, I hypothesized that Rspo1 deficiency stimulates β-cell neogenesis in STZ-diabetes. There was no difference in oral glucose handling between STZ-induced Rspo1mice, although, Rspo1-/- mice demonstrated increased insulin sensitivity compared to wild-type littermates. Moreover, β-cell mass and the total number of islets did not differ between STZ-induced Rspo1+/+ and Rspo1-/- mice, although mice with Rspo1 deficiency had reduced β-cell apoptosis and significantly enhanced numbers of insulin-positive ductal cells suggestive of β-cell neogenesis. Furthermore, the increased β-cell regeneration observed in knockout animals appeared to be associated with a more differentiated/mature β-cell phenotype in Rspo1-/- versus Rspo1+/+ mice. Collectively, these findings indicate a role for Rspo1 as a negative regulator of in vivo β-cell neogenesis and survival in the face of STZ-induced diabetes.

The cWnt activator, Rspondin-1 (Rspo1), has been identified as a regulator of β-cell growth and function, although its role in pathophysiological conditions such as streptozotocin (STZ)-induced diabetes is unknown. Hence, I hypothesized that Rspo1 deficiency stimulates β-cell neogenesis in STZ-diabetes. There was no difference in oral glucose handling between STZ-induced Rspo1mice, although, Rspo1-/- mice demonstrated increased insulin sensitivity compared to wild-type littermates. Moreover, β-cell mass and the total number of islets did not differ between STZ-induced Rspo1+/+ and Rspo1-/- mice, although mice with Rspo1 deficiency had reduced β-cell apoptosis and significantly enhanced numbers of insulin-positive ductal cells suggestive of β-cell neogenesis. Furthermore, the increased β-cell regeneration observed in knockout animals appeared to be associated with a more differentiated/mature β-cell phenotype in Rspo1-/- versus Rspo1+/+ mice. Collectively, these findings indicate a role for Rspo1 as a negative regulator of in vivo β-cell neogenesis and survival in the face of STZ-induced diabetes.