Intrinsic and extrinsic regulation of the proliferation and differentiation of cells in the rodent rostral migratory stream

Abstract

An overriding principle of development is that neurons become permanently postmitotic once they initiate differentiation. Work in our laboratory, however, has provided evidence for a population of progenitor cells in mammalian forebrain that express properties of differentiated neurons, even though they continue to divide. These neuronal progenitor cells are situated in the rostral migratory stream (RMS), which extends from a specialized portion of the subventricular zone surrounding the anterior tip of the lateral ventricle, referred to as the SVZa, to the middle of the olfactory bulb. As SVZa‐derived cells migrate to the olfactory bulb, they undergo cell division, and they never deviate from the RMS. Once they reach their final destinations, they become terminally postmitotic interneurons. This Mini‐Review concerns findings from our recent experiments designed to reveal the intrinsic and extrinsic mechanisms governing the proliferation and differentiation of the unique SVZa neuronal progenitor cells. We have investigated the role(s) of cell cycle regulatory proteins, in particular, the cell cycle inhibitor p19INK4d, in the control of SVZa cell proliferation. Several studies have indicated that cells withdraw from the cell cycle once they express p19INK4d. To begin to investigate whether p19INK4d(+) SVZa‐derived cells are postmitotic, we analyzed the pattern of p19INK4d expression by the cells of the RMS. A pronounced gradient of p19INK4d expression was demonstrated; progressively more cells are p19INK4d immunoreactive as the olfactory bulb is approached. In addition, the capacity of p19INK4d(+) cells to incorporate bromodeoxyuridine was investigated. From the results of these studies, we conclude that SVZa cells in the RMS can successively down‐regulate their expression of p19INK4d as they migrate and that they repeatedly exit and reenter the cell cycle while en route to the olfactory bulb. These studies led us to investigate whether bone morphogenetic proteins (BMPs) are involved in the regulation of SVZa cell proliferation and p19INK4d expression, because, elsewhere in the CNS, BMPs modulate cell proliferation and influence cell fate decisions. To determine the effects of BMP signaling on SVZa cell proliferation and differentiation, we altered the expression of the BMP receptor Ia (BMPR‐Ia) using retrovirally mediated gene transfer. The cells in the SVZa encoding the wild‐type BMPR‐Ia exit the cell cycle and do not appear to migrate through the RMS. Conversely, both within the SVZa and along the RMS, the majority of SVZa‐derived cells encoding a dominant‐negative BMPR‐Ia gene do not express p19INK4d. These findings indicate that p19INK4d expression is suppressed when BMP signaling is inhibited. Furthermore, SVZa‐derived cells with both augmented and inhibited BMP signaling retain their neuronal commitment. Collectively, these studies have revealed that SVZa cell proliferation and differentiation is under the control of several interacting intrinsic and extrinsic factors. © 2002 Wiley‐Liss, Inc.

SMAD pathway mediation of BDNF and TGFβ2 regulation of proliferation and differentiation of hippocampal granule neurons

“…The pluripotency of neural cell progenitors (McConnell and Kaznowski, 1991;Coskun and Luskin, 2002) implies that their ultimate phenotype can be influenced by environmental factors. Phenotypic re-specification has been demonstrated, for Development 132 (14) Research article or Co-SMAD4 is blocked by transfection with their respective dominant-negative (∆) forms (G); similarly, transactivation of 3TP-Lux is blocked in the presence of ∆TGFβ-RII and ∆TRKB (H).…”

The Adult Ventricular–Subventricular Zone (V-SVZ) and Olfactory Bulb (OB) Neurogenesis

“…Interestingly, overexpression of Ngn1 can convert BMP into a neuronal differentiation signal from a gliogenic signal (Sun et al 2001). Along a similar line, in the adult SVZ cellular lineage, BMPs induce astrocyte differentiation in the early precursors while inducing cell-cycle exit and enhanced survival of late lineage neuroblasts (Lim et al 2000;Coskun and Luskin 2002); this difference of BMP activity may be related to differential expression of BMP receptor subtypes at different stages of the V-SVZ neurogenic lineage (Lim et al 2000;Panchision et al 2001). These data illustrate the importance of cell-intrinsic factors in their ability of modify the effect of cell-extrinsic niche factors of the V-SVZ.…”

Acute Psychosocial Stress Reduces Cell Survival in Adult Hippocampal Neurogenesis without Altering Proliferation

“…The fact that there was no change in the percentage of cells reentering the cell cycle at the time of stress is another indicator that proliferation is unaffected by the episode of psychosocial stress. The measure of proliferation between 12 and 24 h after thymidine analog delivery results in coarser resolution of this parameter than if animals had been killed after a shorter interval; however, because the cell cycle of neural progenitor-stem cells in the rodent CNS has been reported to take at least 17 h (Coskun and Luskin, 2002), it is likely that the CldUpositive cell population in experiment 1 primarily reflects a single episode of proliferation within this interval. In fact, the estimate of dual-labeled CldU/IdU-positive cells shows that reentry to the cell cycle within 1 d could not exceed 25% of the proliferation population estimate and is likely much less.…”