Papel de las hdacs de la clase iia en la biología de las células de schwann

Resumo

ABSTRACT The increase in cAMP in Schwann cells, caused by the activation of Gpr126, blocks the expression of c-Jun, and induces the expression of Krox-20, which ends up triggering the myelination of the Peripheral Nervous System. As a result of my doctoral work, we have discovered that increased levels of cAMP in Schwann cells causes nuclear translocation of HDAC4 (a histone deacetylase belonging to class IIa) mediated by phosphorylation of serines S265 / S266 by PKA. Once inside the nucleus, HDAC4 binds to the c-Jun promoter and forms a complex with NcoR1 and recruits HDAC3, a class I histone deacetylase. This deacetylates lysine 9 of histone 3 and blocks cJun expression in Schwann cells. Blocking c-Jun expression forces Schwann cells to exit the cell cycle and activate the genetic program of myelination, driven by Krox-20. Using conditional KOs mouse models for class IIa HDACs, I have shown that the elimination of these proteins in Schwann cells causes a delay in the transition from immature to differentiated cells, producing a delay in the myelination of the Peripheral Nervous System during the post-embryonic development. This delay is probably a consequence of the deficiency in the adequate silencing of c-Jun expression. Furthermore, I have shown that the elimination of class IIa HDACs in Schwann cells causes a delay in remyelination that usually occurs during regeneration of peripheral nerves after injury. The absence of these proteins hinders the silencing of c-Jun, delaying the transition from Schwann cell from repair to myelinating. Furthermore, due to the absence of this repression system, there is an increase in the expression of c-Jun after the damage has occurred, which accelerates the Wallerian degeneration. This doctoral work demonstrates the existence of an epigenetic mechanism, sensitive to cAMP and mediated by HDAC class IIa, that regulates the differentiation of the myelinating Schwann cell.