Nuclear Calcium-VEGFD Signaling Controls Maintenance of Dendrite Arborization Necessary for Memory Formation

Department of Neurobiology, Interdisciplinary Centre for Neurosciences (IZN), University of Heidelberg, INF 364, 69120 Heidelberg, Germany.
Neuron (Impact Factor: 15.05). 07/2011; 71(1):117-30. DOI: 10.1016/j.neuron.2011.04.022
Source: PubMed


The role of neuronal dendrites is to receive and process synaptic inputs. The geometry of the dendritic arbor can undergo neuronal activity-dependent changes that may impact the cognitive abilities of the organism. Here we show that vascular endothelial growth factor D (VEGFD), commonly known as an angiogenic mitogen, controls the total length and complexity of dendrites both in cultured hippocampal neurons and in the adult mouse hippocampus. VEGFD expression is dependent upon basal neuronal activity and requires nuclear calcium-calmodulin-dependent protein kinase IV (CaMKIV) signaling. Suppression of VEGFD expression in the mouse hippocampus by RNA interference causes memory impairments. Thus, nuclear calcium-VEGFD signaling mediates the effect of neuronal activity on the maintenance of dendritic arbors in the adult hippocampus and is required for cognitive functioning. These results suggest that caution be employed in the clinical use of blockers of VEGFD signaling for antiangiogenic cancer therapy.

  • Source
    • "We thus investigated whether depolarizing stimuli could rescue the dendritic phenotype of Lmnb1Δ/Δ neurons. We treated cortical neurons with or without KCl or forskolin, which induce depolarization through distinct mechanisms: calcium and cAMP elevation, respectively (Impey et al., 1998; Wayman et al., 2006; Mauceri et al., 2011). We started treatment from 5 DIV, a critical time for dendrite elongation and branching (Wayman et al., 2006) and measured the length of dendrites and axons 72 h later. "
    [Show abstract] [Hide abstract]
    ABSTRACT: Lamin B1, a key component of the nuclear lamina, plays an important role in brain development and function. A duplication of the human Lamin B1 (LMNB1) gene has been linked to adult-onset autosomal dominant leukodystrophy, while mouse and human loss-of-function mutations in Lamin B1 are susceptibility factors for neural tube defects. In the mouse, experimental ablation of endogenous lamin B1 (Lmnb1) severely impairs embryonic corticogenesis. Here we report that in primary mouse cortical neurons, LMNB1 overexpression reduces axonal outgrowth, while deficiency of endogenous Lmnb1 results in aberrant dendritic development. In the absence of Lmnb1, both the length and complexity of dendrites are reduced and their growth is unresponsive to KCl stimulation. This defective dendritic outgrowth stems from impaired ERK signaling. In Lmnb1-null neurons, ERK is correctly phosphorylated, but phospho-ERK fails to translocate to the nucleus possibly due to delocalization of nuclear pore complexes at the nuclear envelope. Together, these data highlight a previously unrecognized role of Lamin B1 in dendrite development of mouse cortical neurons through regulation of nuclear shuttling of specific signaling molecules and NPC distribution.
    Preview · Article · Oct 2015 · Molecular biology of the cell
  • Source
    • "Although significant research has gone into understanding the risk factors and pathological processes of dementias , little is known about factors contributing to cognitive maintenance throughout aging. It has been suggested that maintenance of cognitive ability over time involves adaptive changes that compensate for deficits such as reduced synaptic plasticity [Blau et al., 2011], which naturally occur with aging [Mauceri et al., 2011; Raz and Rodrigue, 2006]. "
    [Show abstract] [Hide abstract]
    ABSTRACT: Objective Identify genetic factors associated with cognitive maintenance in late life and assess their association with gray matter (GM) volume in brain networks affected in aging. Methods We conducted a genome-wide association study of ∼2.4 M markers to identify modifiers of cognitive trajectories in Caucasian participants (N = 7,328) from two population-based cohorts of non-demented elderly. Standardized measures of global cognitive function (z-scores) over 10 and 6 years were calculated among participants and mixed model regression was used to determine subject-specific cognitive slopes. “Cognitive maintenance” was defined as a change in slope of ≥ 0 and was compared with all cognitive decliners (slope < 0). In an independent cohort of cognitively normal older Caucasians adults (N = 122), top association findings were then used to create genetic scores to assess whether carrying more cognitive maintenance alleles was associated with greater GM volume in specific brain networks using voxel-based morphometry. ResultsThe most significant association was on chromosome 11 (rs7109806, P = 7.8 × 10−8) near RIC3. RIC3 modulates activity of α7 nicotinic acetylcholine receptors, which have been implicated in synaptic plasticity and beta-amyloid binding. In the neuroimaging cohort, carrying more cognitive maintenance alleles was associated with greater volume in the right executive control network (RECN; PFWE = 0.01). Conclusions These findings suggest that there may be genetic loci that promote healthy cognitive aging and that they may do so by conferring robustness to GM in the RECN. Future work is required to validate top candidate genes such as RIC3 for involvement in cognitive maintenance. Hum Brain Mapp, 2014. © 2014 Wiley Periodicals, Inc.
    Full-text · Article · Sep 2014 · Human Brain Mapping
  • Source
    • "Furthermore, VEGF-D plays an important role in neuronal synaptic activity, dendritic length, and in the maintenance of complex dendrite arborization via calcium dependent calcium-calmodulin-dependent protein kinase IV signaling [40]. Inhibition of mouse hippocampal VEGF-D result in memory deficits indicating that calcium dependent VEGF-D signaling is highly important for neuronal function and cognition [40]. Apart from its role in vasculature Ang-2 was also shown to be involved in the regulation of cortical neurogenesis in the telencephelon [39]. "
    [Show abstract] [Hide abstract]
    ABSTRACT: Multiple sclerosis (MS) is associated with ectopic lymphoid follicle formation. Podoplanin+ (lymphatic marker) T helper17 (Th17) cells and B cell aggregates have been implicated in the formation of tertiary lymphoid organs (TLOs) in MS and experimental autoimmune encephalitis (EAE). Since podoplanin expressed by Th17 cells in MS brains is also expressed by lymphatic endothelium, we investigated whether the pathophysiology of MS involves inductions of lymphatic proteins in the inflamed neurovasculature. We assessed the protein levels of lymphatic vessel endothelial hyaluronan receptor and podoplanin, which are specific to the lymphatic system and prospero-homeobox protein-1, angiopoietin-2, vascular endothelial growth factor-D, vascular endothelial growth factor receptor-3, which are expressed by both lymphatic endothelium and neurons. Levels of these proteins were measured in postmortem brains and sera from MS patients, in the myelin proteolipid protein (PLP)-induced EAE and Theiler's murine encephalomyelitis virus (TMEV) induced demyelinating disease (TMEV-IDD) mouse models and in cell culture models of inflamed neurovasculature.Results and conclusions: Intense staining for LYVE-1 was found in neurons of a subset of MS patients using immunohistochemical approaches. The lymphatic protein, podoplanin, was highly expressed in perivascular inflammatory lesions indicating signaling cross-talks between inflamed brain vasculature and lymphatic proteins in MS. The profiles of these proteins in MS patient sera discriminated between relapsing remitting MS from secondary progressive MS and normal patients. The in vivo findings were confirmed in the in vitro cell culture models of neuroinflammation.
    Full-text · Article · Oct 2013 · Journal of Neuroinflammation
Show more