The Central Nervous System contains a myriad of different cell types that in the right numbers receive and integrate information from the environment to generate the appropriate biological responses. A specialized pool of multipotent cells -called neural progenitors- gives rise to this enormous cell diversity in a conserved temporal order. Failure to produce the right composition of neuronal subtypes can result in several mental and physical diseases that range from cognitive disorders to severe brain malformations. The textbook's view has been that the ability of neural progenitors to produce different subtypes of neurons is control by an intrinsic cascade of transcription factors that restricts progenitor competence over time. However, there are reasons to question this view. First, heterochronic transplants of progenitor cells in the neocortex in some conditions are able to produce cell fates according to their host environment. Second, depletion of microRNAs (miRNAs) in the retina and the neocortex restricted neuron progenitor competence in a cell- autonomous manner. Additionally, we have previously described that in the retina, 3 miRNAs (Let-7, miR-9, and miR-125b or LP-miRNAs) are able to control neural progenitor competence. Therefore, we hypothesize that miRNAs are required in cortical neural progenitors, known as radial glia, to restrict progenitor competence and produce the different cell fates present in the adult. First, we will determine the miRNAs differentially expressed in radial glia during development and study their expression and activity at the single- cell level. LP-miRNAs are differentially expressed in radial glia and our preliminary data indicate that they are able to regulate radial glia competence. We will modify the activity of LP-miRNAs and other differentially expressed miRNAs in radial glia and determine their effects on progenitor competence by characterizing the cell fates of their progeny. Finally, we will determine the physiological role of miRNAs on radial glia cell cycle as the molecular mechanism that regulates radial glia competence. The proposed research will identify the miRNAs involved in neural progenitor competence and neuron cell fate determination in the neocortex, and potentially in other areas of the Central Nervous System.
The neural progenitors of the Central Nervous System (CNS) give rise to different classes of neurons and glia in a conserved sequence but the molecular mechanism(s) controlling the temporal progression of the progenitor cells remain mostly unknown. We hypothesize that three miRNAs (Let-7, miR-9, and miR-125b) are responsible for restricting progenitor competence during development of the neocortex. The data obtained will allow us to generate a novel comprehensive model where miRNAs regulate neural progenitor competence and cell fate determination in the neocortex, and potentially in other areas of the CNS.
