ESSENTIAL ROLES OF PEA3 TRANSCRIPTION FACTORS IN NEURONAL CONNECTIVITY PATTERNING INDUCED BY NEUROTROPHINS

DE VINCENTI, ANA PAULA; BRUMOVSKY, PABLO; DE VINCENTI, ANA PAULA; BRUMOVSKY, PABLO; RÍOS, ANTONELLA S.; AQUINO, JORGE; RÍOS, ANTONELLA S.; AQUINO, JORGE; FONTANET, PAULA; LEDDA, FERNANDA; FONTANET, PAULA; LEDDA, FERNANDA

Chascomus

Taller; IV Taller de Biología Celular y del Desarrollo; 2018

Neurotrophins are a family of related proteins involved in the control many aspects of peripheral and central nervous system development. This family comprise 4 members: nerve growth factor (NGF), brain-derived neurotrophic factor (BDNF), neurotrophin 3 (NT3) and neurotrophin 4 (NT4). The identification of transcription factors and downstream target genes that mediate neurotrophin dependent neuronal differentiation and target field innervation is currently a major challenge.We have identified members of the Pea3 transcription factor subfamily, Etv4 and Etv5, as key players of the transcriptional program triggered by the neurotrophic factors to control neuronal differentiation. Here we show that Pea3 transcription factor family members, Etv4 and Etv5, are expressed by different neuronal populations of the peripheral and central nervous system. Real time PCR assays indicated that Etv4 and Etv5 mRNA are induced by the neurotrophins NGF and BDNF in sensory and hippocampal cells respectively, suggesting that they could be involved in the biological responses triggered by these neurotrophic factor molecules. Pharmacological assays revealed that activation of MEK/ERK (MAPK) pathway is required for Etv4 and Etv5 gene induction in response to neurotrophins. Gain and loss of function assays indicated that these transcription factors play an essential role in the establishment of sensory and hippocampal connectivity. We also provide evidence of the physiological relevance of these factors in nervous system development by analysis of transgenic mice deficient in these molecules. Together, these data establish Pea3 transcription factors as essential molecules of the transcriptional program linking neurotrophin signaling to neuronal differentiation.