This proposal is a competitive renewal application for our research program on the role of the Caspase family of proteases, the c-Jun NH2-terminal kinase (JNK), and the phosphatidylserine receptor (PSR) in neuronal apoptosis in brain development and neurological diseases. In the present project, we will extend our research of these signaling pathways with a new emphasis on the mechanism of apoptosis and renewal of neural progenitor cells.
Aim 1 : We will investigate the mechanism downstream of phosphatidylserine and phosphatidylserine receptor (PS-PSR) recognition leading to the apoptosis of neural progenitor cells. We will express PS on the outer cell surface of neural progenitor cells and examine the signaling events following PS-PSR recognition. In addition, we will test whether the disruption of PS-PSR recognition in the embryonic brain will alter the apoptosis of neural progenitor cells.
Aim 2 : We will examine the interaction between the JNK and canonical Wnt/beta-catenin signaling in the decision of self-renewal or cell-cycle exit by neural progenitor cells. We will determine whether the canonical Wnt/beta-catenin pathway mediates self-renewal, and whether JNK activation attenuates the canonical Wnt/ beta-catenin signaling to promote differentiation of the daughter cells.
Aim 3 : We will use a transgenic system to calculate the net increase of adult-generated neurons in the mouse brain. In addition, we will test whether EOF and FGF2 infusion can accelerate adult neurogenesis and attract newly born neurons into stroke damaged brain areas. In summary, the present project is built on our research of JNK, phosphatidylserine receptor (PSR), and canonical Wnt/beta-catenin signaling with an emphasis on the mechanism governing the adjustment of the number of neural progenitor cells (Aim 1), the decision of cell-cycle exit by neural progenitor cells (Aim 2), and the accelerated neurogenesis after brain injury (Aim 3). These studies will enhance our understanding of neural plasticity and functional recovery after brain injury.

National Institute of Health (NIH)
National Institute of Neurological Disorders and Stroke (NINDS)
Research Project (R01)
Project #
Application #
Study Section
Neurogenesis and Cell Fate Study Section (NCF)
Program Officer
Owens, David F
Project Start
Project End
Budget Start
Budget End
Support Year
Fiscal Year
Total Cost
Indirect Cost
Yale University
Schools of Medicine
New Haven
United States
Zip Code
Benoit, Jamie D; Rakic, Pasko; Frick, Karyn M (2015) Prenatal stress induces spatial memory deficits and epigenetic changes in the hippocampus indicative of heterochromatin formation and reduced gene expression. Behav Brain Res 281:1-8
Ayoub, Albert E; Rakic, Pasko (2015) Neuronal misplacement in schizophrenia. Biol Psychiatry 77:925-6
Dominguez, Martin H; Ayoub, Albert E; Rakic, Pasko (2013) POU-III transcription factors (Brn1, Brn2, and Oct6) influence neurogenesis, molecular identity, and migratory destination of upper-layer cells of the cerebral cortex. Cereb Cortex 23:2632-43
Han, Kihoon; Gennarino, Vincenzo Alessandro; Lee, Yoontae et al. (2013) Human-specific regulation of MeCP2 levels in fetal brains by microRNA miR-483-5p. Genes Dev 27:485-90
Arellano, Jon I; Guadiana, Sarah M; Breunig, Joshua J et al. (2012) Development and distribution of neuronal cilia in mouse neocortex. J Comp Neurol 520:848-73
Hashimoto-Torii, Kazue; Kawasawa, Yuka Imamura; Kuhn, Alexandre et al. (2011) Combined transcriptome analysis of fetal human and mouse cerebral cortex exposed to alcohol. Proc Natl Acad Sci U S A 108:4212-7
Liu, Xiuxin; Hashimoto-Torii, Kazue; Torii, Masaaki et al. (2010) Gap junctions/hemichannels modulate interkinetic nuclear migration in the forebrain precursors. J Neurosci 30:4197-209
Rakic, Pasko (2009) Evolution of the neocortex: a perspective from developmental biology. Nat Rev Neurosci 10:724-35
Torii, Masaaki; Hashimoto-Torii, Kazue; Levitt, Pat et al. (2009) Integration of neuronal clones in the radial cortical columns by EphA and ephrin-A signalling. Nature 461:524-8
Burns, Kevin A; Murphy, Brian; Danzer, Steve C et al. (2009) Developmental and post-injury cortical gliogenesis: a genetic fate-mapping study with Nestin-CreER mice. Glia 57:1115-29

Showing the most recent 10 out of 13 publications