of Work: The physiological mechanisms associated with neurogenesis and gliogenesis in the embryonic mammalian CNS have become an area of increasing study. Here, they are being studied using a novel strategy combining surface phenotyping with flow cytometry to access directly the physiological properties emerging during neuronal and glial cell lineage progression. Evidence has accumulated that neurotransmitters like acetylcholine (ACh) and GABA appear during neurogenesis where they are thought to play key roles in this process. During FY2001 neural stem cells and neuronal and glial progenitors were isolated from the embryonic cortex by phenotyping and flow cytometry. Stem cells either self-renewed or differentiated into neurons or glia depending on specific growth factors added to the culture. Clonal analysis showed that over time in culture cells underwent self-regulated lineage progression in the undisturbed microenvironment. Proliferating precursors were contiguous with proliferating progenitors, which were arrayed adjacent to differentiating neurons, astrocytes or oligodendrocytes depending on the lineage. This shows that in vitro all of the developmental signals necessary to generate the different stages of neuronal and glial lineages are conveyed in the microenvironment among the cells. Physiological properties and specific growth factor and neurotransmitter receptor and ion channel functions emerging de novo during cell lineage progression recapitulated those appearing in vivo. Growth factor-mediated Ca2+ signalling and self-renewal both involved several interactive pathways. ACh regulated neuronal progenitor cell but not stem cell proliferation via several muscarinic receptors both in vitro and in vivo. Pharmacological block of cholinergic signaling at muscarinic receptors prevented cells from re-entering the cell-cycle and synthesizing DNA. Instead, the cells underwent apoptosis and died. Thus, ACh plays a key role in cortical progenitor cell expansion. Other research has shown that GABA mediates mitogenic, motogenic and morphogenic roles during cortical neurogenesis. GABA stimulated 1) progenitor cell proliferation acting via GABA(A) receptors, 2) postmitotic neuron migration via GABA(B) and 3) neurite outgrowth of postmigratory cortical neurons via GABA(A) receptors. ACh did not share these latter roles. The morphogenic effects of GABA resulted from constitutive synthesis, transport and release from a surface-accessible compartment. This morphogenic role of GABA disappeared following neurite outgrowth and the formation of functional synapses. In summary, the results show that in the rat two widely distributed neurotransmitters play important mitogenic and/or motogenic and morphogenic roles during neurogenesis before they mediate brief synaptic signals.

Agency
National Institute of Health (NIH)
Institute
National Institute of Neurological Disorders and Stroke (NINDS)
Type
Intramural Research (Z01)
Project #
1Z01NS002019-29
Application #
6502143
Study Section
(LNP)
Project Start
Project End
Budget Start
Budget End
Support Year
29
Fiscal Year
2001
Total Cost
Indirect Cost
City
State
Country
United States
Zip Code
Su, Tung-Ping; Zhang, Lei; Chung, Ming-Yi et al. (2009) Levels of the potential biomarker p11 in peripheral blood cells distinguish patients with PTSD from those with other major psychiatric disorders. J Psychiatr Res 43:1078-85
Nielsen, Joseph A; Lau, Pierre; Maric, Dragan et al. (2009) Integrating microRNA and mRNA expression profiles of neuronal progenitors to identify regulatory networks underlying the onset of cortical neurogenesis. BMC Neurosci 10:98
Lee, Cheol; Gyorgy, Andrea; Maric, Dragan et al. (2008) Members of the NuRD Chromatin Remodeling Complex Interact with AUF1 in Developing Cortical Neurons. Cereb Cortex :
Zhang, L; Li, H; Su, T P et al. (2008) p11 is up-regulated in the forebrain of stressed rats by glucocorticoid acting via two specific glucocorticoid response elements in the p11 promoter. Neuroscience 153:1126-34
Ma, Wu; Tavakoli, Tahereh; Chen, Silvia et al. (2008) Reconstruction of functional cortical-like tissues from neural stem and progenitor cells. Tissue Eng Part A 14:1673-86
Maric, Dragan; Fiorio Pla, Alessandra; Chang, Yoong Hee et al. (2007) Self-renewing and differentiating properties of cortical neural stem cells are selectively regulated by basic fibroblast growth factor (FGF) signaling via specific FGF receptors. J Neurosci 27:1836-52
Nielsen, Joseph A; Maric, Dragan; Lau, Pierre et al. (2006) Identification of a novel oligodendrocyte cell adhesion protein using gene expression profiling. J Neurosci 26:9881-91
Hillion, Joelle A; Li, YiXin; Maric, Dragan et al. (2006) Involvement of Akt in preconditioning-induced tolerance to ischemia in PC12 cells. J Cereb Blood Flow Metab 26:1323-31
Zhang, L; Sukhareva, M; Barker, J L et al. (2005) Direct binding of estradiol enhances Slack (sequence like a calcium-activated potassium channel) channels' activity. Neuroscience 131:275-82
Fiorio Pla, Alessandra; Maric, Dragan; Brazer, So-Ching et al. (2005) Canonical transient receptor potential 1 plays a role in basic fibroblast growth factor (bFGF)/FGF receptor-1-induced Ca2+ entry and embryonic rat neural stem cell proliferation. J Neurosci 25:2687-701

Showing the most recent 10 out of 39 publications