Molecular and cellular development of cortical projection neurons: specification, diversity, and directed differentiation from endogenous progenitors for functional circuit repair

Abstract

Responsible for perception, integration of sensory information, cognitive function, motor control, and consciousness, the complex, yet highly organized, six-layered mammalian neocortex contains distinct classes of neurons. Specific subtypes of cortical projection neurons are selectively vulnerable in distinct neurodegenerative, developmental, and acquired diseases of the central nervous system (CNS), resulting in irreversible functional deficits. Evidence for the existence of progenitors in restricted regions of the adult brain, and integration of new neurons into preexisting neural circuitry, support the feasibility of cellular repair in the CNS. However, functional repair of diseased or injured neuronal circuitry requires detailed understanding of molecular controls over development of neuronal lineages, and manipulation of these controls in progenitors to direct the differentiation of functional neurons with appropriate identity, maturity and circuit connectivity. In this study, I target endogenous cortical progenitors present in postnatal and adult brain to direct their differentiation into corticofugal projection neurons. Application of a select combination of central and complementary transcriptional controls, Ngn2, VP16:Olig2 and Fezf2, in cultured cortical Sox6+/NG2+ progenitors directs acquisition of cardinal morphological, molecular, and electrophysiological features of corticofugal projection neurons. These findings demonstrate the feasibility of achieving subtype-specific differentiation of cortical projection neurons from a widely distributed in vivo neocortical progenitor population. Further, in the framework of this thesis, I describe the ongoing effort to identify key molecular controls over development, diversity and connectivity of corticostriatal projection neurons, which would serve as a solid step toward achieving a holistic view of the establishment of corticostriatal circuitry and its potential dysgenesis in disease.