Proliferation and Differentiation of Median Eminence Oligodendrocyte Precursor Cells Is Required for Normal Function of the Hypothalamo-Pituitary Axis
Presentation Number: OR18-1
Date of Presentation: April 2nd, 2017
Christophe Galichet1, Robin Lovell-Badge2 and Karine Rizzoti*2
1The Francis Crick Institute, London, 2The Francis Crick Institute, London, United Kingdom
The hypothalamo-pituitary axis is an essential regulator of metabolism in vertebrates. Upstream of the axis, the hypothalamus centralizes peripheral information and controls accordingly secretion from the six pituitary endocrine cell types. This control is achieved by hypothalamic neurohormones that are secreted either directly into the pituitary, from axonal termini that reach the gland, or into a bed of capillaries located at the base of the third ventricle, at the median eminence (ME), where the hypophyseal portal system collect and deliver them to the gland. Pituitary hormones act in turn on different endocrine glands, tissues and organs. Consequently, pituitary hormones deficiencies, or hypopituitarism, affect important physiological functions and are associated with significant morbidity.
Mutations in the HMG box transcription factor SOX3, both in human and mice, are associated with hypopituitarism. The etiology of the deficiencies is unclear but we showed that the protein is expressed in the adult murine hypothalamus so its loss is likely to affect this region, and indirectly have an effect on pituitary hormones (1). We have here further investigated the role of SOX3 and we first demonstrate that pituitary hormone deficiencies appear after weaning. Moreover, conditional deletion of the gene confirms the neural origin of the phenotype. In adult hypothalami, SOX3 is mainly expressed in cells lining the third ventricle, especially in tanycytes, specialised glial cells of the ME, recently shown to have stem cell properties (2) and also in Oligodendrocyte Precursor Cells (OPCs) in the body of ME (3). We find that in Sox3 mutants proliferation of these two types of progenitors is affected, exclusively post-weaning, as the hypopituitarism appears. We then analysed OPCs fate by performing lineage-tracing expriments using PDGFRa-CreERT2. In Sox3-null mice we observed that these do not differentiate into oligodendrocytes. We therefore propose that this reduction in OPCs and oligodendrocytes underline development of hypopituitarism in Sox3 mutants, where we observe a reduction in pituitary size post-weaning, likely due to defects in endocrine cell maturation. Our results highlight a previously unrecognised role for ME OPCs, which are likely to play a central role in formation of a mature hypothalamo-pituitary connection.
Nothing to Disclose: CG, RL, KR