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ABSTRACT: There are two major classes of neurons in nervous systems: projection neurons and interneurons. During Drosophila nervous system development, a subpopulation of individual stem/progenitor cells gives rise to both motor neurons and interneurons. However, it remains unknown whether individual stem/progenitor cells in the mammalian brain also have the potential to give rise to both projection neurons and interneurons. Here we present evidence that single mouse neocortical progenitors generated both projection neurons and GABAergic interneurons based on studies using fluorescence-activated cell sorting (to obtain individual progenitors) and in vitro clonal analysis using time-lapse video microscopy and immunostaining. We determined that a subpopulation of individual dorsal pallial progenitors from E11.5 Dlx5/6-cre-IRES-EGFP and GAD67-GFP mice can generate both GFP-negative/Tbr1-positive (GFP(-) /Tbr1+)/Tuj1+ cells and GFP+/Sp8+/calretinin+/Tuj1+ cells. The GFP(-) /Tbr1+/Tuj1+ cells had morphological features of cultured projection neurons. Quantitative analysis of the reconstructed lineage trees derived from single progenitors showed that the projection neuron lineage appeared earlier than the interneuron lineage; however, more interneuron-like cells were produced than projection neuron-like cells. Thus, our results provide direct in vitro evidence that individual progenitors of the mammalian dorsal pallium can generate both projection neurons and interneurons.
Stem Cells 02/2013; · 7.78 Impact Factor
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ABSTRACT: In the past several decades, tremendous progress has been achieved through developmental studies of the central nervous system structures such as the cerebral cortex. The septum, which receives reciprocal connections from a variety of brain structures, contains diverse projection neurons but few interneurons. However, the mechanisms underlying its development remain poorly understood. Here we show that the septum is organized into an onion skin-like structure composed of five groups of neurons. These neurons are parvalbumin, choline acetyltransferase, neuronal nitric oxide synthase, calretinin and calbindin immunoreactive. Using the BrdU birth-dating method, we found that these five groups of neurons in the septum are grossly generated following an outside-in pattern. Interestingly, the distinct molecular identities of these neuronal subtypes correspond to their heterogeneous subpallial origins. Using three specific transgenic mouse lines and focal in utero electroporation of Cre-reporter plasmid, we showed that septal neurons originate from not only local progenitor regions but also neighboring progenitor regions including the medial ganglionic eminence and preoptic area. Thus, the neuronal diversity of the septum is achieved through both temporal and spatial control. Our results also suggest that multiple neuronal subtypes arrive to the septum through both radial and tangential migration. Based on these findings, we proposed a novel developmental model involving multiple spatial-temporal origins of septal neurons. This study presents new perspectives for comprehensively exploring septal functions in brain circuits.
Neuroscience 07/2012; 222:110-23. · 3.38 Impact Factor
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ABSTRACT: Neocortical GABAergic interneurons in rodents originate from subpallial progenitor zones. The majority of mouse neocortical interneurons are derived from the medial and caudal ganglionic eminences (MGE and CGE, respectively) and the preoptic area (POA). It is controversial whether the lateral ganglionic eminence (LGE) also generates neocortical interneurons. Previously it was shown that the transcription factor COUP-TFII is expressed in the CGE; here we show that COUP-TFII is also expressed in the dorsal MGE, dorsal LGE (dMGE and dLGE, respectively) and POA. In the adult neocortex, COUP-TFII+/somatostatin (SOM)+ interneurons are mainly located in layer V. Using a genetic fate mapping approach (Shh-Cre and Nkx2.1-Cre), we demonstrate that the POA and ventral MGE do not give rise to COUP-TFII+ neocortical interneurons, suggesting that the dMGE is the source of COUP-TFII+/SOM+ neocortical interneurons. We also observed a migratory stream of COUP-TFII+/Sp8+ cells emanating from the dLGE and CGE to the neocortex mainly through the subventricular zone at later embryonic stages. Slice culture experiments in which dLGE progenitors were labeled with BrdU provided additional evidence that the dLGE generates neocortical interneurons. While earlier born dMGE-derived COUP-TFII+ interneurons occupy cortical layer V, later born dLGE- and CGE-derived COUP-TFII+ ones preferentially occupy superficial cortical layers. A similar laminar distribution was observed following neonatal transplantation of E14.5 dMGE and E15.5 dLGE. These results provide novel information about interneuron fate and position from spatially and temporally distinct origins in the ganglionic eminences. J. Comp. Neurol., 2012. © 2012 Wiley Periodicals, Inc.
The Journal of Comparative Neurology 07/2012; · 3.81 Impact Factor
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ABSTRACT: Subventricular zone neurogenesis occurs throughout life from rodents to primates, but the existence of a rostral migratory stream of immature neurons in postnatal human brains is controversial. A recent report in Nature (Sanai et al., 2011) identifies two neuronal migratory streams in infant human brains targeting the olfactory bulb and prefrontal cortex.
Cell stem cell 11/2011; 9(5):385-6. · 23.56 Impact Factor
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ABSTRACT: Cortical GABAergic interneurons in rodents originate from subpallial progenitors and tangentially migrate to the cortex. While the majority of mouse neocortical interneurons are derived from the medial and caudal ganglionic eminence (MGE and CGE, respectively), it remains unknown whether the lateral ganglionic eminence (LGE) also contributes to a subpopulation of cortical interneurons. Here, we show that the transcription factor Sp8 is expressed in one-fifth of adult cortical interneurons, which appear to be derived from both the dorsal LGE and the dorsal CGE (dLGE and dCGE, respectively). Compared with the MGE-derived cortical interneurons, dLGE/dCGE-derived Sp8-expressing (Sp8+) ones are born at later embryonic stages with peak production occurring at embryonic day 15.5. They tangentially migrate mainly along the subventricular/intermediate zone (SVZ/IZ) route; some continue to express mitotic markers (Ki67 and PH3) in the neonatal cortical SVZ/IZ. Sp8+ interneurons continue to radially migrate from the SVZ/IZ into the cortical layers at early postnatal stages. In contrast to MGE-derived interneurons, dLGE/dCGE-derived Sp8+ interneurons follow an outside-in layering pattern, preferentially occupying superficial cortical layers.
Cerebral Cortex 10/2011; 22(9):2120-30. · 6.54 Impact Factor
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ABSTRACT: Interneurons in the olfactory bulb (OB) represent a heterogeneous population, which are first produced at embryonic stages and persisting into adulthood. Using the BrdU birthdating method combined with immunostaining for several different neuronal markers, we provide the integrated temporal patterns of distinct mouse OB interneuron production from embryonic day 14 to postnatal day 365. We show that although the majority of OB interneuron subtypes continue to be generated throughout life, most subtypes show a similar "bell-like" temporal production pattern with a peak around birth. Tyrosine hydroxylase and calretinin-expressing interneurons are produced at a relatively low rate in the adult OB, while parvalbumin-expressing (PV+) interneuron production is confined to later embryonic and early postnatal stages. We also show that Dlx5/6-expressing progenitors contribute to PV+ interneurons in the OB. Interestingly, all PV+ interneurons in the external plexiform layer (EPL) express the transcription factor Sp8. Genetic ablation of Sp8 by cre/loxP-based recombination severely reduces the number of PV+ interneurons in the EPL of the OB. Our results suggest that Sp8 is required for the normal production of PV+ interneurons in the EPL of the OB. These data expand our understanding of the temporal and molecular regulation of OB interneuron neurogenesis.
Journal of Neuroscience 06/2011; 31(23):8450-5. · 7.11 Impact Factor
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Congmin Wang,
Fang Liu,
Ying-Ying Liu,
Cai-Hong Zhao,
Yan You,
Lei Wang,
Jingxiao Zhang,
Bin Wei,
Tong Ma,
Qiangqiang Zhang,
Yue Zhang,
Rui Chen,
Hongjun Song, Zhengang Yang
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ABSTRACT: It is of great interest to identify new neurons in the adult human brain, but the persistence of neurogenesis in the subventricular zone (SVZ) and the existence of the rostral migratory stream (RMS)-like pathway in the adult human forebrain remain highly controversial. In the present study, we have described the general configuration of the RMS in adult monkey, fetal human and adult human brains. We provide evidence that neuroblasts exist continuously in the anterior ventral SVZ and RMS of the adult human brain. The neuroblasts appear singly or in pairs without forming chains; they exhibit migratory morphologies and co-express the immature neuronal markers doublecortin, polysialylated neural cell adhesion molecule and βIII-tubulin. Few of these neuroblasts appear to be actively proliferating in the anterior ventral SVZ but none in the RMS, indicating that neuroblasts distributed along the RMS are most likely derived from the ventral SVZ. Interestingly, no neuroblasts are found in the adult human olfactory bulb. Taken together, our data suggest that the SVZ maintains the ability to produce neuroblasts in the adult human brain.
Cell Research 05/2011; 21(11):1534-50. · 8.19 Impact Factor
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Bin Wei,
Yanzhen Nie,
Xiaosu Li,
Congmin Wang,
Tong Ma,
Zengjin Huang,
Miao Tian,
Chifei Sun,
Yuqun Cai,
Yan You,
Fang Liu, Zhengang Yang
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ABSTRACT: Neural stem cells from different regions within the subventricular zone (SVZ) are able to produce several different subtypes of interneurons in the olfactory bulb throughout life. Previous studies have shown that ischemic stroke induces the production of new neurons in the damaged striatum from the SVZ. However, the origins and genetic profiles of these newborn neurons remain largely unknown as SVZ neural stem cells are heterogeneous. In the present study, using a mouse model of perinatal hypoxic-ischemic (H/I) brain injury combined with BrdU labeling methods, we found that, as in rat brains, virtually all newborn neuroblasts that migrate from the SVZ into the ischemic injured striatum exclusively express the transcription factor Sp8. Furthermore, although newborn neuroblasts are plentiful in the damaged striatum, only a few can differentiate into calretinin-expressing (CR+) interneurons that continuously express Sp8. Genetic fate mapping reveals that newly born CR+ interneurons are generated from Emx1-expressing neural stem cells in the dorsal-lateral SVZ. These results suggest that the fate of the Emx1-expressing lineage in the ischemic damaged striatum is restricted. However, when Sp8 was conditionally inactivated in the Emx1-lineage cells, Pax6 was ectopically expressed by a subpopulation of Emx1-derived CR+ cells in the normal and damaged striatum. Interestingly, these cells possessed large cell bodies and long processes. This work identifies the origin of the newly born CR+ interneurons in the damaged striatum after ischemic brain injury.
European Journal of Neuroscience 01/2011; 33(5):819-30. · 3.63 Impact Factor
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Cell Research 11/2010; 21(2):220-2. · 8.19 Impact Factor
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ABSTRACT: In children born prematurely and those surviving cerebral ischemia there are white matter abnormalities that correlate with neurological dysfunction. Since this injury occurs in the immature brain, when the majority of subventricular zone (SVZ) cells generate white matter oligodendrocytes, we sought to study the effect this injury has on gliogenesis from the SVZ. We hypothesized that there is aberrant glial cell generation from the SVZ after neonatal hypoxia ischemia (H/I) that contributes to an increased astrogliogenesis with concomitant oligodendroglial insufficiency. Mechanistically we hypothesized that an increase in specific locally produced cytokines during recovery from injury were modifying the differentiation of glial progenitors towards astrocytes at the expense of the more developmentally-appropriate oligodendrocytes.
For these studies we used the Vannucci H/I rat model where P6 rats are subjected to unilateral common carotid ligation followed by 75 min of systemic hypoxia. Retroviral lineage tracing studies combined with morphological and immunohistochemical analyses revealed the preferential generation of SVZ-derived white matter astrocytes instead of oligodendrocytes post hypoxia/ischemia. Microarray and QRT-PCR analyses of the damaged SVZ showed increased expression of several cytokines and receptors that are known to promote astrocyte differentiation, such as EGF, LIF and TGFbeta1 signaling components. Using gliospheres to model the neonatal SVZ, we evaluated the effects of these cytokines on signal transduction pathways regulating astrocyte generation, proliferation and differentiation. These studies demonstrated that combinations of EGF, LIF and TGFbeta1 reconstituted the increased astrogliogenesis. TGFbeta1-induced Smad 2/3 phosphorylation and the combination of EGF, LIF and TGFbeta1 synergistically increased STAT3 phosphorylation over single or double cytokine combinations. Pharmacologically inhibiting ALK5 signaling in vitro antagonized the TGFbeta1-induced increase in astrocyte generation and antagonizing ALK5 signaling in vivo similarly inhibited astrogliogenesis within the SVZ during recovery from H/I.
Altogether, these data indicate that there is aberrant specification of glial precursors within the neonatal SVZ during recovery from neonatal H/I that is a consequence of altered cytokine signaling. Our studies further suggest that antagonizing the ALK5 receptor will restore the normal pattern of cell differentiation after injury to the immature brain.
PLoS ONE 01/2010; 5(3):e9567. · 4.09 Impact Factor
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ABSTRACT: Pediatric traumatic brain injury (TBI) is a significant and underappreciated societal problem. Whereas many TBI studies have evaluated the mechanisms of cell death after TBI, fewer studies have evaluated the extent to which regeneration is occurring. Here we used a cryoinjury model to damage the somatosensory cortex of rats at postnatal day 6 (P6), P10 and P21. We evaluated the production of new neocortical neurons using a combination of 5-bromo-2-deoxyuridine (BrdU) labeling combined with staining for doublecortin (DCX). BrdU+/DCX+ bipolar cells were observed adjacent to the neocortical lesion, with their processes oriented perpendicular to the pial surface. As the animals aged, both the overall proliferative response as well as the production of neocortical neuroblasts diminished, with P6 animals responding most robustly, P10 animals less strongly, and P21 animals showing a very modest proliferative response and virtually no evidence of neocortical neurogenesis. When BrdU was administered at increasingly delayed intervals after the injury at P6, there was a clear difference in the number of new neuroblasts produced as a function of age, with the greatest number of new neocortical neurons produced between 4 and 7 days after the injury. These studies demonstrate that the immature brain has the capacity to produce neocortical neurons after traumatic injury, but this capacity diminishes as the brain continues to develop. Furthermore, in contrast to moderate hypoxic/ischemic brain damage in the P6 rat, where neurogenesis persists for at least 2 months, the response to cryoinjury is quite different as the neurogenic response diminishes over time.
Developmental Neuroscience 01/2010; 32(5-6):488-98. · 3.63 Impact Factor
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ABSTRACT: Neuroblasts produced by the neural stem cells of the adult subventricular zone (SVZ) migrate into damaged brain areas after stroke or other brain injuries, and previous data have suggested that they generate regionally appropriate new neurons. To classify the types of neurons produced subsequent to ischemic injury, we combined BrdU or virus labeling with multiple neuronal markers to characterize new cells at different times after the induction of stroke. We show that SVZ neuroblasts give rise almost exclusively to calretinin-expressing cells in the damaged striatum, resulting in the accumulation of these cells during long term recovery after stroke. The vast majority of SVZ neuroblasts as well as newly born young and mature neurons in the damaged striatum constitutively express the transcription factor Sp8, but do not express transcription factors characteristic of medium-sized spiny neurons, the primary striatal projection neurons lost after stroke. Our results suggest that adult neuroblasts do not alter their intrinsic differentiation potential after brain injury.
Journal of Neuroscience 05/2009; 29(16):5075-87. · 7.11 Impact Factor
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ABSTRACT: Ischemia-induced striatal neurogenesis from progenitors in the adjacent subventricular zone (SVZ) in young and adult rodents has been reported. However, it has not been established whether the precursors that reside in the SVZ retain the capacity to produce the full range of striatal neurons that has been destroyed. By using a neonatal rat model of hypoxic/ischemic brain damage, we show here that virtually all of the newly produced striatal neurons are calretinin (CR)-immunoreactive (+), but not DARPP-32(+), calbindin-D-28K(+), parvalbumin(+), somatostatin(+), or choline acetyltransferase(+). Retroviral fate-mapping studies confirm that these newly born CR(+) neurons are indeed descendants of the SVZ. Our studies indicate that, although the postnatal SVZ has the capacity to produce a range of neurons, only a subset of this repertoire is manifested in the brain after injury.
The Journal of Comparative Neurology 09/2008; 511(1):19-33. · 3.81 Impact Factor
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Zhengang Yang
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ABSTRACT: Interneurons in the granule cell layer (GCL) and glomerular layer (GL) of the olfactory bulb (OB) are generated from progenitors in the subventricular zone (SVZ) of the lateral ventricle. However, little is known about the origin of interneurons in the external plexiform layer (EPL) of the OB. On the basis of the concept of corticogenesis, I hypothesized that interneurons in the EPL of the rodent OB also originate in the SVZ. In the present study, replication-incompetent retroviruses encoding a marker gene, human placental alkaline phosphatase (AP), were injected into the lateral ventricles of postnatal day 4 Wistar rats to label dividing cells in the SVZ. Two days after injection, some of the AP-labeled cells had migrated into the OB. Five weeks after injection, AP/NeuN double-labeled cells were found not only in the GCL and GL but also in the EPL of the OB. In the EPL, most AP-labeled cells were calcium-binding protein parvalbumin (PV)-immunoreactive (+) interneurons. A subset of these cells was made up of calcium-binding protein calretinin (CR)(+) interneurons. According to their structural features, AP-labeled cells in the EPL were Van Gehuchten cells, multipolar cells, and superficial short-axon cells. Thus, postnatal SVZ progenitors give rise not only to granular and periglomerular interneurons but also to interneurons in the EPL of the OB. Furthermore, these results suggest that SVZ progenitors give rise to virtually all subpopulations of interneurons in the OB.
The Journal of Comparative Neurology 02/2008; 506(2):347-58. · 3.81 Impact Factor
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ABSTRACT: Hypoxia-ischemia is relatively common in human infants. Hypoxia-ischemia can occur as a result of complications associated with prematurity or birth, frequently leading to altered brain development and cognitive and behavioral deficits that persist throughout life. Despite the relative frequency of neonatal hypoxic-ischemic encephalopathy, the immature brain sustains relatively less damage than an adult who experiences a similar crisis of oxygen and nutrient deprivation. Therefore, factors may be present that protect the developing brain. During late gestation, the infant brain encounters high levels of the steroid hormone 17beta-estradiol. This observation, combined with evidence supporting 17beta-estradiol as a neuroprotective agent, led us to hypothesize that increasing the basal level of 17beta-estradiol would reduce the amount of hypoxia-ischemia induced injury to the neonatal brain. To test that hypothesis we administered 17beta-estradiol using either a repeated dosing paradigm or a single dose paradigm to immature male and female rats. Here we show that the repeated dosing paradigm (three doses of 17beta-estradiol) provided approximately 70% protection of the hippocampus, basal ganglia, and amygdala. By contrast, a single administration of 17beta-estradiol 24 h prior to hypoxia-ischemia conferred little protection. The only exception was the pyramidal layer of the female hippocampus, which was modestly protected (16% reduction in damage). The protection afforded by the multiple administrations of 17beta-estradiol was similar for females and males, with the only exception being the male amygdala, which displayed less damage than the female amgydala. We conclude that 17beta-estradiol acts as a potent neuroprotective agent against hypoxia-ischemia induced damage to the developing brain, and that pretreating infants at risk for hypoxic-ischemic injury may be advisable.
Experimental Neurology 01/2008; 208(2):269-76. · 4.70 Impact Factor
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ABSTRACT: Neocortical neurons are sensitive to hypoxic-ischemic (H-I) injuries at term and their demise contributes to neurological disorders. Here we tested the hypothesis that the subventricular zone of the immature brain regenerates neocortical neurons, and that this response is sustained.
Systemic injections of 5-bromo-2'-deoxyuridine (BrdU) and intraventricular injections of replication-deficient retroviruses were used to label newly born cells, and confocal microscopy after immunofluorescence was used to phenotype the new cells from several days to several months after perinatal H-I in the postnatal day 6 rat. Quantitative polymerase chain reaction was used to evaluate chemoattractants, growth factors, and receptors.
Robust production of new neocortical neurons after perinatal H-I occurs. These new neurons are descendants of the subventricular zone, and they colonize the cell-sparse columns produced by the injury to the neocortex. These columns are populated by reactive astrocytes and microglia. Surprisingly, this neuronogenesis is sustained for months. Molecular analyses demonstrated increased neocortical production of insulin-like growth factor-1 and monocyte chemoattractant factor-1 (but statistically insignificant production of erythropoietin, brain-derived neurotrophic factor, glial-derived neurotrophic factor, and transforming growth factor-alpha).
The young nervous system has long been known to possess a greater capacity to recover from injury than the adult system. Our data indicate that H-I injury in the neonatal brain initiates an enduring regenerative response from the subventricular zone. These data suggest that additional mechanisms than those previously surmised contribute to the remarkable ability of the immature brain to recover from injury.
Annals of Neurology 04/2007; 61(3):199-208. · 11.09 Impact Factor
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ABSTRACT: Ischemia-induced production of new striatal neurons in young and adult rodents has been studied. However, it is unclear whether neonatal hypoxic/ischemic (H/I) brain injury-induced neuronogenesis in the striatum is transient or sustained, nor has it been established whether these new neurons arise from progenitors within the striatum or from precursors residing in the adjacent subventricular zone. Here, we report that from 2 weeks to 5 months after H/I there are more doublecortin-positive (Dcx+) cells and Dcx+/NeuN+ cells in the damaged striatum compared to the contralateral striatum. After the S-phase marker 5-bromo-2'-deoxyuridine (BrdU) was injected at both short and long intervals (2 days and 2 months) after H/I to label newly born cells, more BrdU+/Dcx+ and BrdU+/NeuN+ cells were observed in the ipsilateral striatum compared to the contralateral striatum. Retroviral fate-mapping studies demonstrated that these newly born striatal neurons are generated from precursors within the subventricular zone. Altogether, these observations indicate the neonatal brain initiates a prolonged regenerative response from the precursors of the subventricular zone (SVZ) that results in persistent production of new striatal neurons.
Developmental Neuroscience 02/2007; 29(4-5):331-40. · 3.63 Impact Factor
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ABSTRACT: Perinatal hypoxia/ischemia (H/I) is the leading cause of neurologic injury resulting from birth complications. Recent advances in critical care have dramatically improved the survival rate of infants suffering this insult, but approximately 50% of survivors will develop neurologic sequelae such as cerebral palsy, epilepsy or cognitive deficits. Here we demonstrate that tripotential neural stem/progenitor cells (NSPs) participate in the regenerative response to perinatal H/I as their numbers increase 100% by 3 d and that they alter their intrinsic properties to divide using expansive symmetrical cell divisions. We further show that production of new striatal neurons follows the expansion of NSPs. Increased proliferation within the NSP niche occurs at 2 d after perinatal H/I, and the proliferating cells express nestin. Of those stem-cell related genes that change, the membrane receptors Notch1, gp-130, and the epidermal growth factor receptor, as well as the downstream transcription factor Hes5, which stimulate NSP proliferation and regulate stem cellness are induced before NSP expansion. The mechanisms for the reactive expansion of the NSPs reported here reveal potential therapeutic targets that could be exploited to amplify this response, thus enabling endogenous precursors to restore a normal pattern of brain development after perinatal H/I.
Journal of Neuroscience 05/2006; 26(16):4359-69. · 7.11 Impact Factor
