Estrogen and progesterone control the spine dendrite formation through the actin regulators Cortactin and WAVE-1.

UZAIR IVONNE DENISE; FLAMINI MARINA INES; SANCHEZ ANGEL MATIAS

Mar del Plata

Congreso; LXII Reunión Anual de la Sociedad Argentina de Investigación Clínica (SAIC); 2017

Sociedad Argentina de Investigación Clínica (SAIC)

Pyramidal neurons from cortex and hippocampus have thousandsof dendritic spines (DS) that form excitatory synapses. As a consequence,failures in DS formation can lead to an improper cognition,a common feature in neurodegenerative diseases like dementia.Actin nucleation is a fundamental process in DS formation and itdepends on actin regulators. Among them, WAVE1 and Cortactinare key activators of the Arp2/3 complex, ultimate responsible for DSformation. Our previous research has established that 17β-estradiol(E2) and progesterone (P4) modulate several signaling pathwaysleading to WAVE1 phosphorylation and DS formation. However, theprecise molecular mechanisms of this regulation remain to be elucidated.Therefore, we asked ourselves firstly, if Cdk5 Kinase andPP2A phosphatase regulate WAVE1 phosphorylation (their targetprotein) in response to rapid treatments with E2 and P4. Secondly,we evaluated if Cortactin phosphorylation was affected by the sametreatments. To test our hypothesis, we employed primary culture ofembryonic rat cortical neurons, immunofluorescence and westernblot analysis. Our results showed that, after treatments with E2 orP4 (10nM, 20min), the number of DS was significantly increased(over a 50% vs. CON, p˂0,05), indicating that both hormones rapidlymodified neuronal morphology. The increase in the number of DSwas prevented by Roscovitine, a Cdk5 inhibitor, and mimicked byOkadaic Acid, a PP2A inhibitor. These changes were accompaniedby a significantly increase of the phosphorylation patterns of Cdk5Y15,PP2AY307 and WAVE1S397 after E2 and P4 stimulation. Furthermore,we also determined that Cortactin mediates DS formation viaa Rac1/PAK1 cascade, after E2 and P4 treatment. As a conclusion,our results suggest that E2 and P4 exert a dynamic regulation ofneurons morphology by inducing a rapid activation of Cortactin andWAVE1. E2 and P4 can promote DS formation and therefore theycontribute to synaptic plasticity processes.Keywords: E2, P4, WAVE1, cortical neurons