Search results for "Transgenic"
showing 10 items of 552 documents
Primary cilia are required for cerebellar development and Shh-dependent expansion of progenitor pool
2008
Cerebellar granule cell precursors (GCPs), which give rise to the most abundant neuronal type in the mammalian brain, arise from a restricted pool of primary progenitors in the rhombic lip (RL). Sonic hedgehog (Shh) secreted by developing Purkinje cells is essential for the expansion of GCPs and for cerebellar morphogenesis. Recent studies have shown that the primary cilium concentrates components of Shh signaling and that this structure is required for Shh signaling. GCPs have a primary cilium on their surface [Del Cerro, M.P., Snider, R.S. (1972). Studies on the developing cerebellum. II. The ultrastructure of the external granular layer. J Comp Neurol 144, 131-64.]. Here, we show that 1)…
Purkinje cell loss and motor coordination defects in profilin1 mutant mice.
2012
Profilin1 is an actin monomer-binding protein, essential for cytoskeletal dynamics. Based on its broad expression in the brain and the localization at excitatory synapses (hippocampal CA3-CA1 synapse, cerebellar parallel fiber (PF)-Purkinje cell (PC) synapse), an important role for profilin1 in brain development and synapse physiology has been postulated. We recently showed normal physiology of hippocampal CA3-CA1 synapses in the absence of profilin1, but impaired glial cell binding and radial migration of cerebellar granule neurons (CGNs). Consequently, brain-specific inactivation of profilin1 by exploiting conditional mutants and Nestin-mediated cre expression resulted in a cerebellar hyp…
The angiopoietin-Tie2 pathway regulates Purkinje cell dendritic morphogenesis in a cell-autonomous manner.
2021
Neuro-vascular communication is essential to synchronize central nervous system development. Here, we identify angiopoietin/Tie2 as a neuro-vascular signaling axis involved in regulating dendritic morphogenesis of Purkinje cells (PCs). We show that in the developing cerebellum Tie2 expression is not restricted to blood vessels, but it is also present in PCs. Its ligands angiopoietin-1 (Ang1) and angiopoietin-2 (Ang2) are expressed in neural cells and endothelial cells (ECs), respectively. PC-specific deletion of Tie2 results in reduced dendritic arborization, which is recapitulated in neural-specific Ang1-knockout and Ang2 full-knockout mice. Mechanistically, RNA sequencing reveals that Tie…
Making Waves: Initiation and Propagation of Corticothalamic Ca2+ Waves In Vivo
2013
Corticothalamic slow oscillations of neuronal activity determine internal brain states. At least in the cortex, the electrical activity is associated with large neuronal Ca(2+) transients. Here we implemented an optogenetic approach to explore causal features of the generation of slow oscillation-associated Ca(2+) waves in the in vivo mouse brain. We demonstrate that brief optogenetic stimulation (3-20 ms) of a local group of layer 5 cortical neurons is sufficient for the induction of global brain Ca(2+) waves. These Ca(2+) waves are evoked in an all-or-none manner, exhibit refractoriness during repetitive stimulation, and propagate over long distances. By local optogenetic stimulation, we …
Dual effects of increased glycogen synthase kinase-3β activity on adult neurogenesis
2013
Adult neurogenesis, the generation of new neurons during the adulthood, is a process controlled by several kinases and phosphatases among which GSK3β exerts important functions. This protein is particularly abundant in the central nervous system, and its activity deregulation is believed to play a key role in chronic disorders such as Alzheimer's disease. Previously, we reported that in vivo overexpression of GSK3β (Tet/GSK3β mice) causes alterations in adult neurogenesis, leading to a depletion of the neurogenic niches. Here, we have further characterized those alterations, finding a delay in the switching-off of doublecortin marker as well as changes in the survival and death rates of imm…
IL-23-mediated mononuclear phagocyte crosstalk protects mice from Citrobacter rodentium-induced colon immunopathology.
2014
Gut homeostasis and mucosal immune defense rely on the differential contributions of dendritic cells (DC) and macrophages. Here we show that colonic CX3CR1+ mononuclear phagocytes are critical inducers of the innate response to Citrobacter rodentium infection. Specifically, the absence of IL-23 expression in macrophages or CD11b+ DC results in the impairment of IL-22 production and in acute lethality. Highlighting immunopathology as a death cause, infected animals are rescued by the neutralization of IL-12 or IFNγ. Moreover, mice are also protected when the CD103+ CD11b− DC compartment is rendered deficient for IL-12 production. We show that IL-12 production by colonic CD103+ CD11b− DC is r…
Influenza A virus infection inhibits the efficient recruitment of Th2 cells into the airways and the development of airway eosinophilia.
2003
Abstract Most infections with respiratory viruses induce Th1 responses characterized by the generation of Th1 and CD8+ T cells secreting IFN-γ, which in turn have been shown to inhibit the development of Th2 cells. Therefore, it could be expected that respiratory viral infections mediate protection against asthma. However, the opposite seems to be true, because viral infections are often associated with the exacerbation of asthma. For this reason, we investigated what effect an influenza A (flu) virus infection has on the development of asthma. We found that flu infection 1, 3, 6, or 9 wk before allergen airway challenge resulted in a strong suppression of allergen-induced airway eosinophil…
Role of the chemokine decoy receptor D6 in balancing inflammation, immune activation, and antimicrobial resistance in Mycobacterium tuberculosis infe…
2008
D6 is a decoy and scavenger receptor for inflammatory CC chemokines. D6-deficient mice were rapidly killed by intranasal administration of low doses of Mycobacterium tuberculosis. The death of D6(-/-) mice was associated with a dramatic local and systemic inflammatory response with levels of M. tuberculosis colony-forming units similar to control D6-proficient mice. D6-deficient mice showed an increased numbers of mononuclear cells (macrophages, dendritic cells, and CD4 and CD8 T lymphocytes) infiltrating inflamed tissues and lymph nodes, as well as abnormal increased concentrations of CC chemokines (CCL2, CCL3, CCL4, and CCL5) and proinflammatory cytokines (tumor necrosis factor alpha, int…
Satb2 Regulates Callosal Projection Neuron Identity in the Developing Cerebral Cortex
2008
SummarySatb2 is a DNA-binding protein that regulates chromatin organization and gene expression. In the developing brain, Satb2 is expressed in cortical neurons that extend axons across the corpus callosum. To assess the role of Satb2 in neurons, we analyzed mice in which the Satb2 locus was disrupted by insertion of a LacZ gene. In mutant mice, β-galactosidase-labeled axons are absent from the corpus callosum and instead descend along the corticospinal tract. Satb2 mutant neurons acquire expression of Ctip2, a transcription factor that is necessary and sufficient for the extension of subcortical projections by cortical neurons. Conversely, ectopic expression of Satb2 in neural stem cells m…
Haploinsufficiency of Tsc2 Leads to Hyperexcitability of Medial Prefrontal Cortex via Weakening of Tonic GABAB Receptor-mediated Inhibition.
2020
Abstract Loss-of-function mutation in one of the tumor suppressor genes TSC1 or TSC2 is associated with several neurological and psychiatric diseases, including autism spectrum disorders (ASDs). As an imbalance between excitatory and inhibitory neurotransmission, E/I ratio is believed to contribute to the development of these disorders, we investigated synaptic transmission during the first postnatal month using the Tsc2+/− mouse model. Electrophysiological recordings were performed in acute brain slices of medial prefrontal cortex. E/I ratio at postnatal day (P) 15–19 is increased in Tsc2+/− mice as compared with wildtype (WT). At P25–30, facilitated GABAergic transmission reduces E/I rati…