scholarly journals Notch1 control of oligodendrocyte differentiation in the spinal cord

2002 ◽  
Vol 158 (4) ◽  
pp. 709-718 ◽  
Author(s):  
Stéphane Genoud ◽  
Corinna Lappe-Siefke ◽  
Sandra Goebbels ◽  
Freddy Radtke ◽  
Michel Aguet ◽  
...  
Keyword(s):  
Spinal Cord ◽  
Central Nervous System ◽  
Nervous System ◽  
Transgenic Mice ◽  
Oligodendrocyte Differentiation ◽  
Temporal Regulation ◽  
Development And Differentiation ◽  
The Central Nervous System

We have selectively inhibited Notch1 signaling in oligodendrocyte precursors (OPCs) using the Cre/loxP system in transgenic mice to investigate the role of Notch1 in oligodendrocyte (OL) development and differentiation. Early development of OPCs appeared normal in the spinal cord. However, at embryonic day 17.5, premature OL differentiation was observed and ectopic immature OLs were present in the gray matter. At birth, OL apoptosis was strongly increased in Notch1 mutant animals. Premature OL differentiation was also observed in the cerebrum, indicating that Notch1 is required for the correct spatial and temporal regulation of OL differentiation in various regions of the central nervous system. These findings establish a widespread function of Notch1 in the late steps of mammalian OPC development in vivo.

scholarly journals Analyses of temporal regulatory elements of the prosaposin gene in transgenic mice

2003 ◽  
Vol 370 (2) ◽  
pp. 557-566 ◽  
Author(s):  
Ying SUN ◽  
David P. WITTE ◽  
Peng JIN ◽  
Gregory A. GRABOWSKI
Keyword(s):  
Spinal Cord ◽  
Central Nervous System ◽  
Nervous System ◽  
Transgenic Mice ◽  
Peak Level ◽  
Regulatory Elements ◽  
Low Level ◽  
The Central Nervous System ◽  
Flanking Region ◽  
The Brain

The expression of prosaposin is temporally and spatially regulated at transcriptional and post-translational levels. Transgenic mice with various 5′-flanking deletions of the prosaposin promoter fused to luciferase (LUC) reporters were used to define its temporal regulatory region. LUC expression in the transgenic mice carrying constructs with 234bp (234LUC), 310bp (310LUC) or 2400bp (2400LUC) of the 5′-flanking region was analysed in the central nervous system and eye throughout development. For 310LUC and 2400LUC, low-level LUC activity was maintained until embryonal day 18 in brain, eye and spinal cord. The peak level of LUC activity was at birth, with return to a plateau (1/3 of peak) throughout adulthood. Deletion of the region that included the retinoic acid-receptor-related orphan receptor (RORα)-binding site and sequence-specific transcription factor (Sp1) cluster sites (44—310bp) suppressed the peak of activity. By comparison, the peak level for 234LUC was shifted 2 weeks into neonatal life in the brain, but not in the eye, and no peak of activity was observed in the spinal cord. The endogenous prosaposin mRNA in eye, spinal cord and cerebellum had low-level expression before birth and continued to increase into adulthood. In cerebrum, the endogenous mRNA showed similar expression profile to constructs 310LUC, 2400LUC and 234LUC, with the peak expression at 1 week and a decreased level in adult. In the brain of the newborn, 2400LUC was highly expressed in the trigeminal ganglion and brain stem regions when compared with the generalized expression pattern for endogenous prosaposin mRNA. These results suggest that the modifiers (RORα- and Sp1-binding sites) residing within 310bp of the 5′-flanking region mediate developmental regulation in the central nervous system and eye. Additional regulatory elements outside the 5′ region of the 2400bp promoter fragment appear to be essential for the physiological control of the prosaposin locus.

scholarly journals Multiple Immediate-Early Gene-Deficient Herpes Simplex Virus Vectors Allowing Efficient Gene Delivery to Neurons in Culture and Widespread Gene Delivery to the Central Nervous System In Vivo

2001 ◽  
Vol 75 (9) ◽  
pp. 4343-4356 ◽  
Author(s):  
Caroline E. Lilley ◽  
Filitsa Groutsi ◽  
ZiQun Han ◽  
James A. Palmer ◽  
Patrick N. Anderson ◽  
...  
Keyword(s):  
Spinal Cord ◽  
Central Nervous System ◽  
Nervous System ◽  
Gene Delivery ◽  
Transgene Expression ◽  
Retrograde Transport ◽  
Spinal Ganglia ◽  
The Central Nervous System ◽  
Simplex Virus

ABSTRACT Herpes simplex virus (HSV) has several potential advantages as a vector for delivering genes to the nervous system. The virus naturally infects and remains latent in neurons and has evolved the ability of highly efficient retrograde transport from the site of infection at the periphery to the site of latency in the spinal ganglia. HSV is a large virus, potentially allowing the insertion of multiple or very large transgenes. Furthermore, HSV does not integrate into the host chromosome, removing any potential for insertional activation or inactivation of cellular genes. However, the development of HSV vectors for the central nervous system that exploit these properties has been problematical. This has mainly been due to either vector toxicity or an inability to maintain transgene expression. Here we report the development of highly disabled versions of HSV-1 deleted for ICP27, ICP4, and ICP34.5/open reading frame P and with an inactivating mutation in VP16. These viruses express only minimal levels of any of the immediate-early genes in noncomplementing cells. Transgene expression is maintained for extended periods with promoter systems containing elements from the HSV latency-associated transcript promoter (J. A. Palmer et al., J. Virol. 74:5604–5618, 2000). Unlike less-disabled viruses, these vectors allow highly effective gene delivery both to neurons in culture and to the central nervous system in vivo. Gene delivery in vivo is further enhanced by the retrograde transport capabilities of HSV. Here the vector is efficiently transported from the site of inoculation to connected sites within the nervous system. This is demonstrated by gene delivery to both the striatum and substantia nigra following striatal inoculation; to the spinal cord, spinal ganglia, and brainstem following injection into the spinal cord; and to retinal ganglion neurons following injection into the superior colliculus and thalamus.

scholarly journals Rho activation patterns after spinal cord injury and the role of activated Rho in apoptosis in the central nervous system

2003 ◽  
Vol 162 (2) ◽  
pp. 233-243 ◽  
Author(s):  
Catherine I. Dubreuil ◽  
Matthew J. Winton ◽  
Lisa McKerracher
Keyword(s):  
Spinal Cord ◽  
Central Nervous System ◽  
Spinal Cord Injury ◽  
Nervous System ◽  
Axon Growth ◽  
Neurotrophin Receptor ◽  
P75 Neurotrophin Receptor ◽  
Cord Injury ◽  
The Central Nervous System

Growth inhibitory proteins in the central nervous system (CNS) block axon growth and regeneration by signaling to Rho, an intracellular GTPase. It is not known how CNS trauma affects the expression and activation of RhoA. Here we detect GTP-bound RhoA in spinal cord homogenates and report that spinal cord injury (SCI) in both rats and mice activates RhoA over 10-fold in the absence of changes in RhoA expression. In situ Rho-GTP detection revealed that both neurons and glial cells showed Rho activation at SCI lesion sites. Application of a Rho antagonist (C3–05) reversed Rho activation and reduced the number of TUNEL-labeled cells by ∼50% in both injured mouse and rat, showing a role for activated Rho in cell death after CNS injury. Next, we examined the role of the p75 neurotrophin receptor (p75NTR) in Rho signaling. After SCI, an up-regulation of p75NTR was detected by Western blot and observed in both neurons and glia. Treatment with C3–05 blocked the increase in p75NTR expression. Experiments with p75NTR-null mutant mice showed that immediate Rho activation after SCI is p75NTR dependent. Our results indicate that blocking overactivation of Rho after SCI protects cells from p75NTR-dependent apoptosis.

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