B.A. New York University, 2011
MD/PhD Stony Brook University (2020)
Dr. Z. Josh Huang, Cold Spring Harbor Laboratory
Birth time-dependent specification of pyramidal neuron laminar and projection types through intermediate progenitors
Pyramidal neurons (PyNs) comprise the majority of cortical neurons and underlie nearly all aspects of cognitive operations. The progenitor cells that give rise to neocortical PyNs mainly include radial glial cells (RGCs) and intermediate progenitor cells (IPCs) located in the embryonic cerebral ventricle wall. RGCs divide asymmetrically to generate neurons either directly or indirectly through IPCs, which divide symmetrically to produce pairs of PyNs. It remains unclear how progenitor types (e.g. RGCs, IPCs), their lineage progression, and timing of neurogenesis contribute to the specification of diverse PyN subtypes defined by axon projection, connectivity, and physiology. In particular, the role of IPCs in the generation of PyNs is poorly understood. The T-domain transcription factor (Tbr2) is specifically expressed in cortical IPCs. We have generated an inducible Tbr2-CreER mouse driver, which allows comprehensive lineage tracing from IPCs and have developed a novel genetic method to fate-map neurons according to their lineage and precise birth time. We have used the Tbr2-CreER driver and Cre-dependent reporter mice to fate map IPCs throughout embryogenesis. In addition to assessing the laminar position of PyN subtypes, axon projections are analyzed with a novel method utilizing viral labeling of fate-mapped PyNs. Using retrograde virus along with our genetic driver and reporter lines allows us to restrict cell labeling by progenitor type, birth date, and projection target. With this method, we can further elucidate the PyN subtypes born from IPCs throughout neurogenesis, using axon projection as more descriptive definition of cell type than laminar location. Fate mapping experiments revealed that IPCs sequentially gave rise to PyNs with distinct laminar patterns spanning multiple nonconsecutive layers with only a trend towards an inside-out sequence. This suggests that IPCs do not generate PyNs in a strictly inside-out manner. Rather, temporal cohorts of multiple fate-restricted IPCs simultaneously, as well as sequentially, generate PyN subtypes defined by their axon projection and laminar location. These findings begin to link progenitor type and their time of neurogenesis to the specification of PyN subtypes.
NIMH F30 NRSA
(MSTP-supported publications indicated with an *)
*Kim Y, Yang GR, Pradhan K, Venkataraju KU, Bota M, García Del Molino LC, Fitzgerald G, Ram K, He M, Levine JM, Mitra P, Huang ZJ, Wang XJ, Osten P (2017). Strategies and Tools for Combinatorial Targeting of GABAergic Neurons in Mouse Cerebral Cortex. Cell. 171(2):456-469.e22.
*He M, Tucciarone J, Lee S, Nigro MJ, Kim Y, Levine JM, Kelly SM, Krugikov I, Wu P, Chen Y, Gong L, Hou Y, Osten P, Rudy B, Huang ZJ (2016). Strategies and Tools for Combinatorial Targeting of GABAergic Neurons in Mouse Cerebral Cortex. Neuron. 91(6):1228-1243.