ESPE Abstracts (2018) 89 FC13.4

The Kallman Syndrome Gene Product is Specifically Expressed in ACTH-Expressing Cells and Dysplays Sexual Dimorphism Expression in Human Fetal Pituitary

Fabien Guimiota,b, Adeline Bonnarda, Nadia Soussi-Yaniscostasb, Carol Schnollb & Nicolas de Rouxb,a

aRobert Debré Hospital, AP-HP, Paris, France; bINSERM U1141, Paris, France

Kallman syndrome is defined by the association of anosmia due to an agenesis of the olfactory bulbs and hypogonadotropic hypogonadism due to a GnRH deficiency which is currently explained by a deficit of GnRH neuron migration from the olfactory placode toward the hypothalamus. In fact, the X-linked form of KS is due to loss of function mutations in ANOS1 which encodes an extracellular protein (ANOSMIN) interacting with cell membrane heparin sulfate proteoglycans but also growth factor receptors. ANOSMIN has been implicated in cell-cell adhesion, axon guidance, neurite outgrowth as well as differentiation of neuronal progenitors within cranial placodes. However, associated developmental defects are relatively frequent in KS patients suggesting that ANOSMIN may participate to other developmental pathways. Recently, we observed an expression of ANOS1 in fetal human pituitary mRNA microarray. The aim of this study was to characterize the pituitary expression of ANOS1 during development in human fetus. We first confirmed ANOS1 expression in fetal anterior pituitaries by RT-qPCR along pituitary development. Our results revealed a higher expression of ANOS1 in female pituitaries when compared to males during the second trimester of development and a peak of expression of ANOS1 at midgestation in males. Two antibodies directed against different domains of ANOSMIN showed an intracellular staining in a minority of hormonal cells. To specify the cell types expressing ANOSMIN, a dual immunostaining was performed with an antibody against ANOSMIN and an antibody against each anterior pituitary hormone. ANOSMIN staining was restrained to intracellular vesicles of ACTH expressing cells. Surprisingly, these ANOSMIN/ACTH cells were also positive for SOX2, a marker of stem cell. The expression of SOX2 was in fact only observed in ACTH+ cells. This study has revealed a fine control of ANOS1 expression during pituitary development. It also showed an unexpected expression of ANOSMIN in corticotropes. Altogether, these studies raise two interesting questions: 1/ What could be the molecular function of ANOSMIN in corticotropes. 2/ Do ACTH expressing cells have stem cell potential compared to other pituitary hormonal cells ?

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