Phenotypic Differentiation during Migration of Dopaminergic Progenitor Cells to the Olfactory Bulb

Type B coxsackieviruses (CVB) frequently infect the CNS and, together with other enteroviruses, are the most common cause of viral meningitis in humans. Newborn infants are particularly vulnerable, and CVB also can infect the fetus, leading to mortality, or to neurodevelopmental defects in surviving infants. Using a mouse model of neonatal CVB infection, we previously demonstrated that coxsackievirus B3 (CVB3) could infect neuronal progenitor cells in the subventricular zone (SVZ). Here we extend these findings, and we show that CVB3 targets actively proliferating (bromodeoxyuridine ϩ , Ki67 ϩ ) cells in the SVZ, including type B and type A stem cells. However, infected cells exiting the SVZ have lost their proliferative capacity, in contrast to their uninfected companions. Despite being proliferation deficient, the infected neuronal precursors could migrate along the rostral migratory stream and radial glia, to reach their final destinations in the olfactory bulb or cerebral cortex. Furthermore, infection did not prevent cell differentiation, as determined by cellular morphology and the expression of maturation markers. These data lead us to propose a model of CVB infection of the developing CNS, which may explain the neurodevelopmental defects that result from fetal infection.

Section: Discussionsupporting

confidence: 86%

Coxsackievirus Targets Proliferating Neuronal Progenitor Cells in the Neonatal CNS

Feuer¹,

Pagarigan²,

Harkins³

et al. 2005

“…Given the potential clinical importance of dopaminergic cell production from adult progenitors (Baker et al, 2001), we investigated Pax6 expression patterns during adult SVZ neurogenesis. We found that Pax6 was expressed in most proliferating SVZ progenitors but only in a subpopulation of migrating neuroblasts, indicating that migrating neuroblasts are molecularly heterogeneous.…”

Section: In Pax6mentioning

confidence: 99%

Pax6 Is Required for Making Specific Subpopulations of Granule and Periglomerular Neurons in the Olfactory Bulb

Kohwi¹,

Osumi²,

Rubenstein³

et al. 2005

299

298

Sey/Sey progenitors produce neuroblasts capable of migrating into the OB but fail to generate dopaminergic periglomerular and superficial granule cells. Interestingly, superficial granule neurons also express mRNA for tyrosine hydroxylase, the rate-limiting enzyme in dopamine synthesis. Our data show that SVZ neuroblasts are heterogeneous and that Pax6 is required in a cell-autonomous manner for the production of cells in the dopaminergic lineage.

“…Neuronal differentiation of SVZ neuroblasts initiates early during radial migration and passes through a unique sequence of events involving the expression of neurotransmitter receptors and rate-limiting enzymes in neurotransmitters biosynthesis (Baker et al, 2001;Carleton et al, 2003). For instance, the transcription of the tyrosine hydroxylase gene occurs in SVZ newly generated cells before they attain their final periglomerular position (Baker et al, 2001;Saino-Saito et al, 2004).…”

mentioning

confidence: 99%

cAMP Response Element-Binding Protein Regulates Differentiation and Survival of Newborn Neurons in the Olfactory Bulb

Giachino¹,

Marchis²,

Giampietro³

et al. 2005

142

133

The transcription factor cAMP response element-binding protein (CREB) is involved in multiple aspects of neuronal development and plasticity. Here, we demonstrate that CREB regulates specific phases of adult neurogenesis in the subventricular zone/olfactory bulb (SVZ/OB) system. Combining immunohistochemistry with bromodeoxyuridine treatments, cell tracer injections, cell transplants, and quantitative analyses, we show that although CREB is expressed by the SVZ neuroblasts throughout the neurogenic process, its phosphorylation is transient and parallels neuronal differentiation, increasing during the late phase of tangential migration and decreasing after dendrite elongation and spine formation. In vitro, inhibition of CREB function impairs morphological differentiation of SVZderived neuroblasts. Transgenic mice lacking CREB, in a null CREM genetic background, show reduced survival of newborn neurons in the OB. This finding is further supported by peripheral afferent denervation experiments resulting in downregulation of CREB phosphorylation in neuroblasts, the survival of which appears heavily impaired. Together, these findings provide evidence that CREB regulates differentiation and survival of newborn neurons in the OB.