Cyclin-dependent kinase 4 (cdk4) regulates the myelin sheath of hypothalamic neurons

S. Geller*^a (Dr), S. Gaspari^a (Dr), R. Dreos^a (Dr), V. Barquissau^a (Dr), K. Huber^a (Dr), D. Ziegler^a (Dr), I. Lopez-Mejia^a (Prof), L. Fajas^a (Prof)

^a UNIL, Lausanne, SWITZERLAND

* sarah.geller@unil.ch

The hypothalamus is the control center for many homeostatic mechanisms. Recent data obtained by our group and others suggested that Cyclin-dependent Kinase 4 (CDK4) could be a key factor in the regulation of hypothalamic regulation. Inhibition of CDK4 expression and/or activity in the hypothalamus altered fat mass gain as well as cold resistance in mice. CDK4 is a critical cell cycle regulator, cell differentiation and cell metabolism. However, the role(s) and function(s) of CDK4 in the brain, particularly in the hypothalamus, are not well known. The objectives of this study are to determine the cell types expressing CDK4 and the role of this protein in the adult hypothalamus.

We found that in the adult hypothalamus, CDK4 is mainly expressed by glial cells such as oligodendrocytes progenitors (OPC), mature oligodendrocytes and astrocytes. These cell types are mainly involved in myelin synthesis and maintenance. Adult male mice deleted for CDK4 (CDK4-KO) were used to explore the role of the protein in hypothalamic myelin. Hypothalami of CDK4-KO mice not only exhibit lower expression of genes involved in myelin compound/synthesis but also less myelin content. CDK4-KO mice displayed a lower percentage of axons myelinated at the level of projection of oxytocin and vasopressin neurons in the median eminence (ME). In contrast, we do not show any difference in the number of OPC and oligodendrocytes. However, the ultrastructure of myelin differs dramatically between both genotypes. Electron microscopy confirms a higher myelin g-ratio; suggesting that myelinated axons should display reduced condition velocity compared to the control littermate.

CDK4-Ko mice present a defect of myelin sheath of hypothalamic neurons which seems independent from default in oligodendrocytes ontogenesis. As myelin formation and maintenance involve lipid and cholesterol metabolism of glial cells; we currently explore the role of CDK4 in this process. Mice deleted for CDK4 specifically in glial cells will be used to determine the involvement of cell-autonomous mechanism or cell-cell interaction. This work will not only illustrate a new function of CDK4 but will also help us to better understand myelin regulation and its importance in hypothalamic physio-pathological functions

The author has declared no conflict of interest.