Estudi dels coactivadors transcripcionals de creb (crtcs) en neurones i astròcits

• Autores: Laura Rubio Ferrarons
• Directores de la Tesis: Carlos A. Saura Antolín (dir. tes.)
• Lectura: En la Universitat Autònoma de Barcelona ( España ) en 2020
• Idioma: español
• ISBN: 9788449098093
• Tribunal Calificador de la Tesis: Silvia Ginés Padros (presid.), José Ramon Bayascas Ramírez (secret.), Albert Giralt Torroella (voc.)
• Programa de doctorado: Programa de Doctorado en Neurociencias por la Universidad Autónoma de Barcelona
• Enlaces
  • Tesis en acceso abierto en: TDX
• Resumen

  • The transcriptional function of the cyclic adenosine monophosphate (cAMP)-response element binding protein (CREB) is modulated by the family of CREB regulated transcription coactivators (CRTCs). CRTC isoforms (CRTC1, CRTC2 and CRTC3) are present in the brain, but their specific expression, regulation and function in the distinct cell types of the brain remain largely unclear. In this doctoral thesis, I have investigated the expression pattern, regulatory mechanisms and transcriptional function of the CRTC1 and CRTC2 isoforms in neurons and astrocytes of the mouse cerebral cortex. Using novel Crtc2-LacZ reporter mice, I show that CRTC2 is expressed in the adult mouse brain in both neurons and glial cells, including microglia and astrocytes. CRTC1 is abundant in neurons, whereas CRTC2 is highly expressed in cultured astrocytes. Pharmacological analyses reveal differential regulation of CRTC1 and CRTC2 in cultured neurons and astrocytes. In neurons, synaptic activity induces CRTC1 dephosphorylation and activation through protein phosphatase (PP) 2B/calcineurin while CRTC2 dephosphorylation is mediated by PP1. In astrocytes, CRTC1 dephosphorylation is regulated by PP2B/calcineurin, whereas CRTC2 dephosphorylation is independent of PP2B/calcineurin, PP1 and PP2A activities. In agreement, CRTC1 is dephosphorylated upon neuronal activity and translocated to the nucleus where interacts with CREB to enhance gene transcription. CRTC2 is also translocated to the nucleus after neuronal stimulation without affecting CREB-mediated transcription in cortical neurons. In fact, neuronal CRTC2 deletion does not result in global phenotypic alterations in neuron-specific Crtc2 conditional knockout (cKO) mice. By contrast, CRTC2 is translocated to nucleus and recruited to specific CREB target gene promoters to mediate activity-induced transcription in astrocytes. These results indicate differential expression, regulatory mechanisms and transcriptional roles of CRTC isoforms in neurons and astrocytes of the cerebral cortex.