Becoming a new neuron in the cerebral cortex

Abstract

Neocortical neurons are born from progenitors situated in the ventricular zone (VZ) and migrate to the cortex to form circuits that underlie mammalian high skilled behavior. Genetic programs that broadly specify distinct subtypes of neurons within the neocortex are increasingly understood. But despite the mounting evidence on how different genes regulate different aspects of cortical neurogenesis and neuron differentiation, the genetic program that drives acquisition and maintenance of neuronal identity upon progenitor division is unknown. It is thus important to dissect the proper sequence of molecular events that occurs during acquisition of neuronal identity. A major limitation in studying this has been the inability to specifically identify, access and track specific cohort of neurons from their time of birth in vivo with the requisite temporal resolution. To overcome this obstacle, I have developed and standardized a novel technique “FlashTag” that enables precise in vivo tagging of isochronic cohorts of VZ-born neurons and progenitors from the time of mitosis. By combining this high temporal resolution “FlashTag” technology with single-cell RNA sequencing, we have identified and functionally characterized neuron-specific primordial transcriptional programs as they dynamically unfold in vivo during the first forty-eight hours following mitosis. Our results provide a detailed functional account of early neuronal life, including the discovery of successive “transcriptional waves” that organize the temporal sequence of cellular differentiation events. This high-resolution dynamic blueprint of neuronal specification can identify the transient molecular events that guide a neuron towards its final fate, and contribute to a roadmap for the reverse engineering of specific classes of cortical neurons from undifferentiated cells