Fate Specification in the Developing Forebrain
One of the most fundamental challenges in developmental biology is understanding how the vast numbers of different cell types in an organism are specified from stem cells. In the central nervous system, one solution to this problem is to establish spatially segregated germinal zones dedicated to produce specific cell types. However, all excitatory projection neuron subtypes in the cerebral cortex ultimately derive from the same germinal zone. During early development, neural stem cells in this zone transform into progenitors called radial glial cells (RGCs), which then generate all cortical excitatory projection neurons. Thus, a central question in cortical development has been how all of these different subtypes of projection neurons are specified from RGCs. Previously, the prevailing model proposed that there is a single kind of multipotent RGC that generates all the different classes of projection neurons in a time-dependent manner. Indeed, the subtype identity of a projection neuron roughly correlates with the time of cell-cycle exit of its progenitor (i.e., its “birth date”). Therefore, this model proposes that the potential of a common progenitor is progressively restricted over time, such that the birth date of a neuron determines its subtype fate. This model has been the cornerstone of projection neuron fate-specification for the past 20 years.
Our studies have led to a new model for how different classes of cortical projection neurons are specified. Using genetic fate-mapping experiments in vivo, we showed that there are at least 2 distinct subtypes of RGCs that are fate-restricted to generate different functional classes of excitatory projection neurons. Importantly, this restriction is in place even before the progenitors begin making neurons, indicating a model in which some aspects of fate specification are initiated at the earliest stages of forebrain development from neural stem cells. These findings challenge the prevailing “common progenitor” hypothesis and raise a number of very intriguing new questions about how diversity among cortical cell types is achieved during embryonic development. The precise molecular and cellular mechanisms of early fate-specification are now being actively investigated in our lab. In addition, several projects in our lab aim to determine whether this early fate restriction is unique to cortical projection neurons, or is a more universal principle applicable to other types of neuronal and glial cell types throughout the CNS.
Our studies have led to a new model for how different classes of cortical projection neurons are specified. Using genetic fate-mapping experiments in vivo, we showed that there are at least 2 distinct subtypes of RGCs that are fate-restricted to generate different functional classes of excitatory projection neurons. Importantly, this restriction is in place even before the progenitors begin making neurons, indicating a model in which some aspects of fate specification are initiated at the earliest stages of forebrain development from neural stem cells. These findings challenge the prevailing “common progenitor” hypothesis and raise a number of very intriguing new questions about how diversity among cortical cell types is achieved during embryonic development. The precise molecular and cellular mechanisms of early fate-specification are now being actively investigated in our lab. In addition, several projects in our lab aim to determine whether this early fate restriction is unique to cortical projection neurons, or is a more universal principle applicable to other types of neuronal and glial cell types throughout the CNS.
