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The Journal of Neuroscience, November 16, 2005, 25(46):10747-10758; doi:10.1523/JNEUROSCI.2662-05.2005

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Development/Plasticity/Repair
CCAAT/Enhancer-Binding Protein Phosphorylation Biases Cortical Precursors to Generate Neurons Rather Than Astrocytes In Vivo

Annie Paquin,^1,2,3 Fanie Barnabé-Heider,^1,2,6 Ryoichiro Kageyama,⁷ and Freda D. Miller^1,2,3,4,5,6

¹Developmental Biology and ²Brain and Behavior Groups, Hospital for Sick Children, ³Institute of Medical Sciences, and Departments of ⁴Molecular and Medical Genetics and ⁵Physiology, University of Toronto, Toronto, Canada M5G 1X8, ⁶Department of Neurology and Neurosurgery, McGill University, Montreal, Canada H3A 2B4, and ⁷Virology Institute, Kyoto University, Kyoto 606-8507, Japan

The intracellular mechanisms that bias mammalian neural precursors to generate neurons versus glial cells are not well understood. We demonstrated previously that the growth factor-regulated mitogen-activated protein kinase kinase (MEK) and its downstream target, the CCAAT/enhancer-binding protein (C/EBP) family of transcription factors, are essential for neurogenesis in cultured cortical precursor cells (Ménard et al., 2002). Here, we examined a role for this pathway during cortical cell fate determination in vivo using in utero electroporation of the embryonic cortex. These studies demonstrate that inhibition of the activity of either MEK or the C/EBPs inhibits the genesis of neurons in vivo. Moreover, the MEK pathway mediates phosphorylation of C/EBP in cortical precursors, and expression of a C/EBP construct in which the MEK pathway phosphorylation sites are mutated inhibits neurogenesis. Conversely, expression of a C/EBP construct, in which the same sites are mutated to glutamate and therefore are "constitutively" phosphorylated, enhances neurogenesis in the early embryonic cortex. A subpopulation of precursors in which C/EBP activity is inhibited are maintained as cycling precursors in the ventricular/subventricular zone of the cortex until early in postnatal life, when they have an enhanced propensity to generate astrocytes, presumably in response to gliogenic signals in the neonatal environment. Thus, activation of an MEK-C/EBP pathway in cortical precursors in vivo biases them to become neurons and against becoming astrocytes, thereby acting as a growth factor-regulated switch.

Key words: neural stem cells; MEK; in utero electroporation; neurogenesis; gliogenesis; cortical development; ERK; transcription factors

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Received June 28, 2005; revised October 4, 2005; accepted October 5, 2005.

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				H. Ishikawa, V. Fencki, E. E. Marsh, P. Yin, D. Chen, Y.-H. Cheng, S. Reisterd, Z. Lin, and S. E. Bulun CCAAT/Enhancer Binding Protein {beta} Regulates Aromatase Expression via Multiple and Novel Cis-Regulatory Sequences in Uterine Leiomyoma J. Clin. Endocrinol. Metab., March 1, 2008; 93(3): 981 - 991. [Abstract] [Full Text] [PDF]

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