Neuronal Cell Fate Determination
Generation of the mammalian central nervous system
(CNS) requires the production of a large variety of glial and neuronal cell types at the correct numbers and
appropriate positions. These diverse cell types arise from multipotent progenitor cells whose controlled
proliferation, migration, and differentiation are critical for proper development. Genetic studies in a number
of model systems have demonstrated that a small number of proneural genes that encode transcription factors
of the basic-helix-loop-helix (bHLH) family play a key role in regulating the development of neuronal lineages
from uncommitted progenitors. Thus, bHLH factors have key roles in neural development, affecting both the timing
of differentiation and the specification of cell fate.
Our laboratory has investigated the control of cell fate specification in the developing mammalian brain by both extrinsic and intrinsic genetic determinants, focusing on the role of the Neurogenin (Ngn) sub-family of proneural bHLH transcription factors in the central nervous system (CNS). In the developing cortex, Neurogenin1 (Ngn1) is expressed together with Ngn2 transiently and selectively in dorsal telencephalic progenitors within the ventricular zone. While initial ectopic expression studies indicated a role for Ngns in neurogenesis, we have found that Ngn1 also inhibits the differentiation of neural stem cells into astrocytes. While Ngn1 promotes neurogenesis by functioning as a transcriptional activator, Ngn1 inhibits astrocyte differentiation by sequestering the CBP-Smad1 transcription complex away from astrocyte differentiation genes, and by inhibiting the activation of STAT transcription factors that are necessary for gliogenesis. Thus, two distinct mechanisms are involved in the activation and suppression of gene expression during cell-fate specification by neurogenin. Further study has revealed new roles for these factors in several aspects of neural development, including the timing of cell cycle exit, cell migration, neuronal connectivity, and the specification of neuronal subtype identity in the developing CNS.
Bonni A, Sun Y, Nadal-Vicens M, Bhatt A, Frank DA, Rozovsky I, Stahl N, Yancopoulos GD, Greenberg ME. Regulation of gliogenesis in the central nervous system by the JAK-STAT signaling pathway. Science 1997; 278(5337):477-483.
Sun Y, Nadal-Vicens M, Misono S, Lin MZ, Zubiaga A, Hua X, Fan G, Greenberg ME. Neurogenin promotes neurogenesis and inhibits glial differentiation by independent mechanisms. Cell 2001; 104(3):365-376.
Ross SE, Greenberg ME, Stiles CD Basic helix-loop-helix factors in cortical development. Neuron 2003; 39(1):13-25. Review.
Other research areas:
Activity-Dependent Gene Transcription
Regulation of Translation in Neurons
Neuronal Survival and Apoptosis
Synapse Formation and Maintenance
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