The role of neuregulin–ErbB4 interactions on the proliferation and organization of cells in the subventricular zone

Abstract

Coordinated regulation of neuronal progenitor differentiation in the subventricular zone (SVZ) is a fundamental feature of adult neurogenesis. However, the molecular control of this process remains mostly undeciphered. Here, we investigate the role of neuregulins (NRGs) in this process and show that a NRG receptor, ErbB4, is primarily expressed by polysialylated neural cell adhesion molecule immature neuroblasts but is also detected in a subset of GFAP ؉ astroglial cells, ependymal cells, and Dlx2 ؉ precursors in the SVZ. Of the NRG ligands, both NRG1 and -2 are expressed by immature polysialylated neural cell adhesion molecule neuroblasts in the SVZ. NRG2 is also expressed by some of the GFAP ؉ putative stem cells lining the ventricles. Infusion of exogenous NRG1 leads to rapid aggregation of Dlx2 ؉ cells in the SVZ and affects the initiation and maintenance of organized neuroblast migration from the SVZ toward the olfactory bulb. In contrast, the infusion of NRG2 increased the number of Sox2 and GFAP ؉ precursors in the SVZ. An outcome of this NRG2 effect is an increase in the number of newly generated migrating neuroblasts in the rostral migratory stream and GABAergic interneurons in the olfactory bulb. The analysis of conditional null mice that lack NRG receptor, ErbB4, in the nervous system revealed that the observed activities of NRG2 require ErbB4 activation. These results indicate that different NRG ligands affect distinct populations of differentiating neural precursors in the neurogenic regions of the mature forebrain. Furthermore, these studies identify NRG2 as a factor capable of promoting SVZ proliferation, leading to the formation of new neurons in vivo.adult neurogenesis ͉ rostral migratory stream ͉ schizophrenia T he primary sites of neurogenesis in the adult rodent brain are in the hippocampus and the forebrain subventricular zone [SVZ (1-9)]. The multipotential cells in the SVZ are believed to give rise to a collection of migrating neural progenitors that form the rostral migratory stream (RMS). These cells transit from the anterior SVZ to the olfactory bulb and appear to migrate tangentially along each other through tubes composed of astrocytic-like glial cells (3, 4). Upon their arrival at the posterior core of the olfactory bulb, the cells exit the RMS, switch from a tangential to radial mode of migration, and differentiate into functional granule interneurons or periglomerular interneurons (10, 11).The observation that the receptor tyrosine kinase ErbB4 is selectively expressed at high levels in the SVZ and RMS (12) suggests a possible role for the ErbB4 ligands, the neuregulins (NRGs), as modulators of the proliferation and migration of neural stem and progenitor cells. The NRGs are a collection of related polypeptides characterized by the presence of a single EGF-like domain, capable of binding to and activating ErbB receptors, of which there are four members, ErbB1-4. NRGs serve as ligands for ErbB4 (13) and ErbB3 (14-16) but can be potent activators of ErbB2 and weak activators of the E...

Cdk6-Dependent Regulation of G1 Length Controls Adult Neurogenesis

“…We then defined whether Cdk6 deficiency would also preferentially affect the proliferation of a particular subpopulation of precursors of the SVZ. Using Sox2 as a marker of type B cells in the SVZ [28,29], we first observed that the numbers of Sox2 þ /Ki-67 þ cells were not impaired in the absence of Cdk6 (Supporting Information Fig. 7).…”

Molecular dissection of NRG1-ERBB4 signaling implicates PTPRZ1 as a potential schizophrenia susceptibility gene

“…[8][9][10][11] ERBB4 plays a critical role in the development of the brain, and has been shown to directly influence the proliferation, organization and migration of cells in the rostral migratory stream. [12][13][14] There is now emerging evidence that the gene for ERBB4 also influences risk for schizophrenia, 15,16 especially when considered together with NRG1. 16 Moreover, there is evidence from postmortem mRNA studies for alterations in the levels of ERBB4 15 (as well as the ERBB3 coreceptor [17][18][19][20][21] ) in schizophrenia.…”

Stroke-Induced Subventricular Zone Proliferation is Promoted by Tumor Necrosis Factor-α-Converting Enzyme Protease Activity

“…Subventricular zone cells express several substrates for TACE proteolysis in addition to APP and TNFa (Doetsch et al, 2002;Ghashghaei et al, 2006;Stump et al, 2002). In fact, several TACE-cleaved EGFR proligands represent attractive candidates for TACE-mediated SVZ neurogenesis as well (Doetsch et al, 2002;Jin et al, 2004;Stump et al, 2002).…”