Regulation of Cerebral Cortical Size by Control of Cell Cycle Exit in Neural Precursors

Brigham and Women's Hospital, Boston, Massachusetts, United States
Science (Impact Factor: 33.61). 08/2002; 297(5580):365-9. DOI: 10.1126/science.1074192
Source: PubMed


Transgenic mice expressing a stabilized β-catenin in neural precursors develop enlarged brains with increased cerebral cortical
surface area and folds resembling sulci and gyri of higher mammals. Brains from transgenic animals have enlarged lateral ventricles
lined with neuroepithelial precursor cells, reflecting an expansion of the precursor population. Compared with wild-type precursors,
a greater proportion of transgenic precursors reenter the cell cycle after mitosis. These results show that β-catenin can
function in the decision of precursors to proliferate or differentiate during mammalian neuronal development and suggest that
β-catenin can regulate cerebral cortical size by controlling the generation of neural precursor cells.

Download full-text


Available from: Anjen Chenn
  • Source
    • "In this regard, experiments showed that a disturbance of the balance between self-renewal and differentiation of mouse NPCs promotes cortical expansion (Chenn and Walsh, 2002). In this study, transgenic mice expressing a stabilized β-catenin in NPCs develop enlarged brains with increased cerebral cortical surface area and folds resembling sulci and gyri of higher mammals (Chenn and Walsh, 2002), suggesting that the precise regulation of the proliferative state of either NPC maintenance or NPC differentiation maybe a critical factor for regulating cerebral cortical size during evolution. How this regulation is orchestrated has been a topic of interest, and many researchers have been investigating it from various standpoints. "
    [Show abstract] [Hide abstract]
    ABSTRACT: Glutamatergic neurons of the mammalian cerebral cortex originate from radial glia (RG) progenitors in the ventricular zone (VZ). During corticogenesis, neuroblasts migrate toward the pial surface using two different migration modes. One is multipolar (MP) migration with random directional movement, and the other is locomotion, which is a unidirectional movement guided by the RG fiber. After reaching their final destination, the neurons finalize their migration by terminal translocation, which is followed by maturation via dendrite extension to initiate synaptogenesis and thereby complete neural circuit formation. This switching of migration modes during cortical development is unique in mammals, which suggests that the RG-guided locomotion mode may contribute to the evolution of the mammalian neocortical 6-layer structure. Many factors have been reported to be involved in the regulation of this radial neuronal migration process. In general, the radial migration can be largely divided into four steps; (1) maintenance and departure from the VZ of neural progenitor cells, (2) MP migration and transition to bipolar cells, (3) RG-guided locomotion, and (4) terminal translocation and dendrite maturation. Among these, many different gene mutations or knockdown effects have resulted in failure of the MP to bipolar transition (step 2), suggesting that it is a critical step, particularly in radial migration. Moreover, this transition occurs at the subplate layer. In this review, we summarize recent advances in our understanding of the molecular mechanisms underlying each of these steps. Finally, we discuss the evolutionary aspects of neuronal migration in corticogenesis.
    Preview · Article · Jan 2016 · Frontiers in Neuroscience
    • "However, if CSF is drained from early embryonic brains, the walls of the embryonic telencephalon (and other brain regions) buckle inward (Desmond & Jacobson 1977) (Supplemental Figure 3), just as the buckling shell models predict. Similar folds emerge in transgenic mice whose telencephalic progenitors divide abnormally often, causing increased tangential expansion of the proliferative zone (Chenn & Walsh 2002) (Supplemental Figure 1). Because the ventricles in these transgenic mice do not expand in concert with the telencephalic wall, the wall must fold. "
    [Show abstract] [Hide abstract]
    ABSTRACT: Why the cerebral cortex folds in some mammals but not in others has long fascinated and mystified neurobiologists. Over the past century-especially the past decade-researchers have used theory and experiment to support different folding mechanisms such as tissue buckling from mechanical stress, axon tethering, localized proliferation, and external constraints. In this review, we synthesize these mechanisms into a unifying framework and introduce a hitherto unappreciated mechanism, the radial intercalation of new neurons at the top of the cortical plate, as a likely proximate force for tangential expansion that then leads to cortical folding. The interplay between radial intercalation and various biasing factors, such as local variations in proliferation rate and connectivity, can explain the formation of both random and stereotypically positioned folds. Expected final online publication date for the Annual Review of Neuroscience Volume 38 is July 08, 2015. Please see for revised estimates.
    No preview · Article · Apr 2015 · Annual Review of Neuroscience
  • Source
    • "Knockdown of GPR50 results in suppressing neuronal differentiation and self-renewal, which is accompanied with increased hes1 and decreased TCF7L2 expression. Both pathways promote self-renewal through enhancing cyclin D1 transcription [20] [21] [28]. It seems that decreased TCF7L2 overrides the effects of increased hes1 on self-renewal of NPCs. "
    [Show abstract] [Hide abstract]
    ABSTRACT: G protein-coupled receptor 50 (GPR50), a risk factor for major depressive disorder and bipolar affective disorder, is expressed in both the developmental and adult brain. However, the function of GPR50 in the brain remains unknown. We here show GPR50 is expressed by neural progenitor cells (NPCs) in the ventricular zone of embryonic brain. Knockdown of GPR50 with a small interference RNA (siRNA) decreased self-renewal and neuronal differentiation, but not glial differentiation of NPCs. Moreover, overexpression of either full-length GPR50 or the intracellular domain of GPR50, rather than the truncated GPR50 in which the intracellular domain is deleted in, increased neuronal differentiation, indicating that GPR50 promotes neuronal differentiation of NPCs in an intracellular domain-dependent manner. We further described that the transcriptional activity of the intracellular domain of notch on Hes1 gene was repressed by overexpression of GPR50. In addition, decreased levels of transcription factor 7-like 2 (TCF7L2) mRNA was observed in GPR50 siRNA-transfected NPCs, suggesting that knockdown of GPR50 impairs wnt/β-catenin signaling. Moreover, the mRNA levels of neurogenin (Ngn) 1, Ngn2 and cyclin D1, the target genes of notch and wnt/β-catenin signalings, in NPCs were reduced by knockdown of GPR50. Therefore, GPR50 promotes self-renewal and neuronal differentiation of NPCs possibly through regulation of notch and wnt/β-catenin signalings. Copyright © 2015. Published by Elsevier Inc.
    Preview · Article · Feb 2015 · Biochemical and Biophysical Research Communications
Show more