The cerebral cortex performs complex cognitive functions at the expense of tremendous energy consumption. Blood vessels in the brain are known to form stereotypic patterns that facilitate efficient ...oxygen and nutrient delivery. Yet little is known about how vessel development in the brain is normally regulated. Radial glial neural progenitors are well known for their central role in orchestrating brain neurogenesis. Here we show that, in the late embryonic cortex, radial glial neural progenitors also play a key role in brain angiogenesis, by interacting with nascent blood vessels and regulating vessel stabilization via modulation of canonical Wnt signaling. We find that ablation of radial glia results in vessel regression, concomitant with ectopic activation of Wnt signaling in endothelial cells. Direct activation of Wnt signaling also results in similar vessel regression, while attenuation of Wnt signaling substantially suppresses regression. Radial glial ablation and ectopic Wnt pathway activation leads to elevated endothelial expression of matrix metalloproteinases, while inhibition of metalloproteinase activity significantly suppresses vessel regression. These results thus reveal a previously unrecognized role of radial glial progenitors in stabilizing nascent brain vascular network and provide novel insights into the molecular cascades through which target neural tissues regulate vessel stabilization and patterning during development and throughout life.
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DOBA, IZUM, KILJ, NUK, PILJ, PNG, SAZU, SIK, UILJ, UKNU, UL, UM, UPUK
Both the cadherin-catenin complex and Rho-family GTPases have been shown to regulate dendrite development. We show here a role for p120 catenin (p120ctn) in regulating spine and synapse formation in ...the developing mouse brain.
p120catenin gene deletion in hippocampal pyramidal neurons in vivo resulted in reduced spine and synapse densities along dendrites. In addition, p120 catenin loss resulted in reduced cadherin levels and misregulation of Rho-family GTPases, with decreased Rac1 and increased RhoA activity. Analyses in vitro indicate that the reduced spine density reflects aberrant Rho-family GTPase signaling, whereas the effects on spine maturation appear to result from reduced cadherin levels and possibly aberrant Rho-family GTPase signaling. Thus, p120ctn acts as a signal coordinator between cadherins and Rho-family GTPases to regulate cytoskeletal changes required during spine and synapse development.
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GEOZS, IJS, IMTLJ, KILJ, KISLJ, NLZOH, NUK, OILJ, PNG, SAZU, SBCE, SBJE, UILJ, UL, UM, UPCLJ, UPUK, ZAGLJ, ZRSKP
To study mechanisms that regulate the construction of inhibitory circuits, we examined the role of brain-derived neurotrophic factor (BDNF) in the assembly of GABAergic inhibitory synapses in the ...mouse cerebellar cortex. We show that within the cerebellum, BDNF-expressing cells are restricted to the internal granular layer (IGL), but that the BDNF protein is present within mossy fibers which originate from cells located outside of the cerebellum. In contrast to deletion of TrkB, the cognate receptor for BDNF, deletion of Bdnf from cerebellar cell bodies alone did not perturb the localization of pre- or postsynaptic constituents at the GABAergic synapses formed by Golgi cell axons on granule cell dendrites within the IGL. Instead, we found that BDNF derived from excitatory mossy fiber endings controls their differentiation. Our findings thus indicate that cerebellar BDNF is derived primarily from excitatory neurons--precerebellar nuclei/spinal cord neurons that give rise to mossy fibers--and promotes GABAergic synapse formation as a result of release from axons. Thus, within the cerebellum the preferential localization of BDNF to axons enhances the specificity through which BDNF promotes GABAergic synaptic differentiation.
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IZUM, KILJ, NUK, PILJ, PNG, SAZU, UL, UM, UPUK
In the peripheral nervous system, target tissues control the final size of innervating neuronal populations by producing limited amounts of survival-promoting neurotrophic factors during development. ...However, it remains largely unknown if the same principle works to regulate the size of neuronal populations in the developing brain. Here we show that neurotrophin signaling mediated by the TrkB receptor controls striatal size by promoting the survival of developing medium-sized spiny neurons (MSNs). Selective deletion of the gene for the TrkB receptor in striatal progenitors, using the Dlx5/6-Cre transgene, led to a hindpaw-clasping phenotype and a 50% loss of MSNs without affecting striatal interneurons. This loss resulted mainly from increased apoptosis of newborn MSNs within their birthplace, the lateral ganglionic eminence. Among MSNs, those expressing the dopamine receptor D2 (DRD2) were most affected, as indicated by a drastic loss of these neurons and specific down-regulation of the DRD2 and enkephalin. This specific phenotype of mutant animals is likely due to preferential TrkB expression in DRD2 MSNs. These findings suggest that neurotrophins can control the size of neuronal populations in the brain by promoting the survival of newborn neurons before they migrate to their final destinations.
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BFBNIB, NMLJ, NUK, PNG, SAZU, UL, UM, UPUK
The melanocortin-4 receptor (MC4R) is critically involved in regulating energy balance, and obesity has been observed in mice with mutations in the gene for brain-derived neurotrophic factor (BDNF). ...Here we report that BDNF is expressed at high levels in the ventromedial hypothalamus (VMH) where its expression is regulated by nutritional state and by MC4R signaling. In addition, similar to MC4R mutants, mouse mutants that expresses the BDNF receptor TrkB at a quarter of the normal amount showed hyperphagia and excessive weight gain on higher-fat diets. Furthermore, BDNF infusion into the brain suppressed the hyperphagia and excessive weight gain observed on higher-fat diets in mice with deficient MC4R signaling. These results show that MC4R signaling controls BDNF expression in the VMH and support the hypothesis that BDNF is an important effector through which MC4R signaling controls energy balance.
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DOBA, IZUM, KILJ, NUK, PILJ, PNG, SAZU, UILJ, UKNU, UL, UM, UPUK
We showed previously that loss of the integrin β8 subunit, which forms αvβ8 heterodimers, results in abnormal vascular development in the yolk sac, placenta, and brain. Animals lacking the integrin ...β8 (
itg
β
8
) gene die either at midgestation, because of insufficient vascularization of the placenta and yolk sac, or shortly after birth with severe intracerebral hemorrhage. To specifically focus on the role of integrins containing the β8 subunit in the brain, and to avoid early lethalities, we used a targeted deletion strategy to delete
itg
β
8
only from cell types within the brain. Ablating
itg
β
8
from vascular endothelial cells or from migrating neurons did not result in cerebral hemorrhage. Targeted deletion of
itg
β
8
from the neuroepithelium, however, resulted in bilateral hemorrhage at postnatal day 0, although the phenotype was less severe than in
itg
β
8
-null animals. Newborn mice lacking
itg
β
8
from the neuroepithelium had hemorrhages in the cortex, ganglionic eminence, and thalamus, as well as abnormal vascular morphogenesis, and disorganized glia. Interestingly, adult mice lacking
itg
β
8
from cells derived from the neuroepithelium did not show signs of hemorrhage. We propose that defective association between vascular endothelial cells and glia lacking
itg
β
8
is responsible for the leaky vasculature seen during development but that an unidentified compensatory mechanism repairs the vasculature after birth.
Integrins are a large family of cell adhesion receptors involved in a variety of cellular functions. To study their roles at central synapses, we used two
cre
recombinase lines to delete the
Itgb1
β1 ...integrin gene in forebrain excitatory neurons at different developmental stages. Removal of the β1 integrins at an embryonic stage resulted in severe cortical lamination defects without affecting the cellular organization of pyramidal neurons in the CA3 and CA1 regions of the hippocampus. Whereas the hippocampal neurons underwent normal dendritic and synaptic differentiation, the adult synapses exhibited deficits in responses to high-frequency stimulation (HFS), as well as in long-term potentiation (LTP). Deletion of β1 integrin at a later postnatal stage also impaired LTP but not synaptic responses to HFS. Thus, the β1-class integrins appear to play distinct roles at different stages of synaptic development, critical for the proper maturation of readily releasable pool of vesicles during early development but essential for LTP throughout adult life.
Lung cancer is the leading cause of cancer death in the world, but the molecular mechanisms for its development have not been well characterized. The suppressors of cytokine signaling (SOCS) are ...inhibitors of cytokine signaling that function via the Janus kinase (JAK)/signal transducers and activators of transcription (STAT) pathway. Eight SOCS proteins with similar structures have been identified so far. SOCS family members, however, have distinct mechanisms of inhibition of JAK/STAT signaling. Abnormalities of the JAK/STAT pathway are associated with cancer. Inhibition of signaling results in growth suppression in various cell types. Recently, the involvement of SOCS-1 in carcinogenesis has been reported. Here, we report identification of frequent hypermethylation in CpG islands of the functional SOCS-3 promoter that correlates with its transcription silencing in cell lines (lung cancer, breast cancer, and mesothelioma) and primary lung cancer tissue samples. Restoration of SOCS-3 in lung cancer cells where SOCS-3 was methylation-silenced resulted in the down-regulation of active STAT3, induction of apoptosis, and growth suppression. Our results suggest that methylation silencing of SOCS-3 is one of the important mechanisms of constitutive activation of the JAK/STAT pathway in cancer pathogenesis. The data also suggest that SOCS-3 therapy may be useful in the treatment of cancer.
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BFBNIB, NMLJ, NUK, PNG, SAZU, UL, UM, UPUK
In order to assess the in vivo function of integrins containing the β8 subunit, we have generated integrin β8-deficient mice. Ablation of β8 results in embryonic or perinatal lethality with profound ...defects in vascular development. Sixty-five percent of integrin β8-deficient embryos die at midgestation, with evidence of insufficient vascularization of the placenta and yolk sac. The remaining 35% die shortly after birth with extensive intracerebral hemorrhage. Examination of brain tissue from integrin β8-deficient embryos reveals abnormal vascular morphogenesis resulting in distended and leaky capillary vessels, as well as aberrant brain capillary patterning. In addition, endothelial cell hyperplasia is found in these mutant brains. Expression studies show that integrin β8 transcripts are localized in endodermal cells surrounding endothelium in the yolk sac and in periventricular cells of the neuroepithelium in the brain. We propose that integrin β8 is required for vascular morphogenesis by providing proper cues for capillary growth in both yolk sac and embryonic brain. This study thus identifies a molecule crucial for vascular patterning in embryonic yolk sac and brain.
Targeted deletion of
focal adhesion kinase (
fak) in the developing dorsal forebrain resulted in local disruptions of the cortical basement membrane located between the neuroepithelium and ...pia-meninges. At disruption sites, clusters of neurons invaded the marginal zone. Retraction of radial glial endfeet, midline fusion of brain hemispheres, and gliosis also occurred, similar to type II cobblestone lissencephaly as seen in congenital muscular dystrophy. Interestingly, targeted deletion of
fak in neurons alone did not result in cortical ectopias, indicating that
fak deletion from glia is required for neuronal mislocalization. Unexpectedly,
fak deletion specifically from meningeal fibroblasts elicited similar cortical ectopias in vivo and altered laminin organization in vitro. These observations provide compelling evidence that FAK plays a key signaling role in cortical basement membrane assembly and/or remodeling. In addition, FAK is required within neurons during development because neuron-specific
fak deletion alters dendritic morphology in the absence of lamination defects.
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GEOZS, IJS, IMTLJ, KILJ, KISLJ, NLZOH, NUK, OILJ, PNG, SAZU, SBCE, SBJE, UILJ, UL, UM, UPCLJ, UPUK, ZAGLJ, ZRSKP
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