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ABSTRACT: Multiple congenital contractures, also known as fetal akinesia deformation sequence (FADS) and related terms, result from decreased fetal movement. The underlying etiologies are diverse and include central nervous system (CNS) dysgeneses and primary myopathies. Persistent central nuclei or the presence of myotubes is often regarded as evidence of a primary myopathic etiology; however, these findings are also associated with impaired fetal innervation. We report 7 fetuses, estimated gestational age 20 to 23 weeks, with persistent myotubular morphology, a change that could be (mis)interpreted as a primary myopathy. In 4 of the patients, CNS histology showed hypoxic/ischemic injury, polymicrogyria, mineralized neurons, and microinfarcts with or without loss of anterior horn neurons. FADS cases with polymicrogyria have frequently been interpreted as a consequence of a primary brain malformation. Only a few descriptions of FADS associate polymicrogyria with CNS hypoxic/ischemic injury, however, and do not describe skeletal muscle maturation delay. We hypothesize that this combination of neural and muscular pathology is an under-recognized pattern in FADS, which results from diffuse hypoxic/ischemic injury involving the brain and spinal cord during early to middle gestation.
Pediatric and Developmental Pathology 12/2009; 13(3):192-201. · 0.99 Impact Factor
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ABSTRACT: Prostaglandin E2 is one of several eicosanoid products of the cyclooxygenase isozymes and is a key regulator of innate immune responses; it also possesses paracrine effects on mature neurons. The prostaglandin E2 receptor family consists of four subtypes of which EP1 and EP2 are known to be expressed by microglia. Lipopolysaccharide (LPS)-induced innate immune activation leads to the degeneration of intermediate progenitor cells (IPCs) that are destined for neuronal maturation in the hippocampal subgranular zone (SGZ); these cells can be identified by the expression of the transcription factor T-box brain gene 2 (Tbr2). Importantly, depletion of LPS-induced IPCs from the SGZ is suppressed by cyclooxygenase inhibitors. We therefore tested the hypothesis that either EP1 or EP2 is critical to LPS-induced depletion of Tbr2+ IPCs from the SGZ. Expression of either EP1 or EP2 was necessary for Toll-like receptor 4-dependent innate immune-mediated depletion of these Tbr2+ IPCs in mice. Moreover, EP1 activation was directly toxic to murine adult hippocampal progenitor cells; EP2 was not expressed by these cells. Finally, EP1 modulated the response of murine primary microglia cultures to LPS but in a manner distinct from EP2. These results indicate that prostaglandin E2 signaling via either EP1 or EP2 is largely to completely necessary for Toll-like receptor 4-dependent depletion of IPCs from the SGZ and suggest further pharmacological strategies to protect this important neurogenic niche.
American Journal Of Pathology 05/2009; 174(6):2300-9. · 4.89 Impact Factor
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ABSTRACT: There is evidence for interaction between the developing circulatory and nervous systems. Blood vessels provide a supporting niche in regions of adult neurogenesis. Here we present a systematic analysis of vascular development in the embryonic murine cortex and demonstrate that dividing cells, including Tbr2-positive intermediate progenitor cells, are closer to the vasculature than expected from a random distribution. To examine whether neurites of the newly generated embryonic neurons find blood vessels as an attractive and permissive substrate, we overlayed green fluorescent protein (GFP)-labeled dissociated cortical progenitors on embryonic organotypic cortical slice cultures with labeled vasculature. Our observations of neurites extending toward and along labeled blood vessels support the notion of vascular-neuronal interactions. The altered cortical layering had no obvious effect on the vascular patterns within the cortical plate (CP) in shaking rat Kawasaki (SRK) and the reeler mutant mouse at the ages studied (E19 and P3). It appears that similarly to other neurogenic regions in the adult, the embryonic "vascular niche" might influence neural progenitor cells during telencephalic neurogenesis, neuronal migration, and neurite extension, but the laminar phenotype of cell classes within the CP has limited influence on the developing vasculature.
Cerebral Cortex 05/2009; 19 Suppl 1:i32-41. · 6.54 Impact Factor
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Paige Cundiff,
Lidong Liu,
Yupeng Wang,
Junhui Zou,
Yung-Wei Pan,
Glen Abel,
Xin Duan,
Guo-Li Ming,
Chris Englund, Robert Hevner,
Zhengui Xia
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ABSTRACT: The commitment of multi-potent cortical progenitors to a neuronal fate depends on the transient induction of the basic-helix-loop-helix (bHLH) family of transcription factors including Neurogenin 1 (Neurog1). Previous studies have focused on mechanisms that control the expression of these proteins while little is known about whether their pro-neural activities can be regulated by kinase signaling pathways. Using primary cultures and ex vivo slice cultures, here we report that both the transcriptional and pro-neural activities of Neurog1 are regulated by extracellular signal-regulated kinase (ERK) 5 signaling in cortical progenitors. Activation of ERK5 potentiated, while blocking ERK5 inhibited Neurog1-induced neurogenesis. Furthermore, endogenous ERK5 activity was required for Neurog1-initiated transcription. Interestingly, ERK5 activation was sufficient to induce Neurog1 phosphorylation and ERK5 directly phosphorylated Neurog1 in vitro. We identified S179/S208 as putative ERK5 phosphorylation sites in Neurog1. Mutations of S179/S208 to alanines inhibited the transcriptional and pro-neural activities of Neurog1. Our data identify ERK5 phosphorylation of Neurog1 as a novel mechanism regulating neuronal fate commitment of cortical progenitors.
PLoS ONE 02/2009; 4(4):e5204. · 4.09 Impact Factor
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ABSTRACT: Transplantation of human fetal neural tissue into adult neostriatum is an experimental therapy for Huntington's disease (HD). Here we describe a patient with HD who received ten intrastriatal human fetal neural transplants and, at one site, an autologous sural nerve co-graft. Although initially clinically stable, she developed worsening asymmetric upper motor neuron symptoms in addition to progression of HD, and ultimately died 121 months post transplantation. Eight neural transplants, up to 2.9 cm, and three ependymal cysts, up to 2.0 cm, were identified. The autologous sural nerve co-graft was found adjacent to the largest mass lesion, which, along with the ependymal cyst, exhibited pronounced mass effect on the internal capsules bilaterally. Grafts were composed of neurons and glia embedded in disorganized neuropil; robust Y chromosome labeling was present in a subset of grafts and cysts. The graft-host border was discrete, and there was no evidence of graft rejection or HD pathologic changes within donor neurons. This report, for the first time, highlights the potential for graft overgrowth in a patient receiving fetal neural transplantation.
Acta Neuropathologica 01/2009; 117(3):329-38. · 9.32 Impact Factor
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Journal of Neurosurgery Spine 01/2007; 5(6):555. · 1.53 Impact Factor
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The Lancet Neurology 10/2003; 2(9):567-71. · 23.46 Impact Factor
