Funció de la via de senyalització de pdk1 depenent del pif-pocket durant la corticogenesi embrionària

• Autores: Sònia Pascual Guiral
• Directores de la Tesis: Jose R. Bayascas (dir. tes.)
• Lectura: En la Universitat Autònoma de Barcelona ( España ) en 2020
• Idioma: español
• ISBN: 9788449097829
• Tribunal Calificador de la Tesis: Joaquím Egea Navarro (presid.), Elisenda Sanz Iglesias (secret.), Marta Pascual (voc.)
• Programa de doctorado: Programa de Doctorado en Neurociencias por la Universidad Autónoma de Barcelona
• Enlaces
  • Tesis en acceso abierto en: TDX
• Resumen

  • The 3-Phosphoinositide-dependent protein kinase 1 (PDK1) is the master kinase that coordinates the PI3K signalling pathway by activating 23 kinases of the AGC family, including PKB. PDK1 acts after recognizing a conserved docking site on its substrates, once it has been previously phosphorylated by a different kinase. PKB is the only exception that does not require this interaction to be fully activated by PDK1. A mutant form of PDK1, leucine at position 155 to glutamic acid (L155E), in which the pocket recognizing the substrate-docking site was disrupted, was created and expressed in neuron-specific conditional knock-in mice. This mutation disrupted all PI3K-dependent signalling but PKB, which was activated normally. Previous results showed that the resulting adult mutant miceexhibited reduced neuronal polarization and differentiation in vitro, as well as abnormal neuronal positioning and diminished neuronal connectivity in the cortex and hippocampus in vivo. Here it is demonstrated that the PDK1 L155E mutation causes microcephaly. Intermediate progenitors (IPs) are reduced in number by the expression of the PDK1 L155E mutation during neurodevelopment, and mitosis is reduced in their predecessors, the apical progenitors (APs). However, the generation of deep layers immature Tbr1-positive neurons is increased, which do not translate into an increased pool of their derived Ctip2-positive specified neurons, that are actually diminished. Surprisingly, layering is maintained correctly. To elucidate in the future the possible specific role of ribosomal protein S6 kinase (S6K) in neurodevelopment as the key PDK1 efector, a novel double phosphomimetic construct, S6KT229D/T389D, was created, which confirmed to work independently of both PDK1 and mTORC1 in a constitutively active manner.