Temporal Regulation of Dendritic Spines Through NrCAM-Semaphorin3F Receptor Signaling in Developing Cortical Pyramidal Neurons

Mohan, Vishwa; Sullivan, Chelsea S.; Guo, Jiqing; Wade, Sarah D.; Majumder, Samarpan; Agarwal, Amit; Anton, E. S.; Temple, Brenda; Maness, Patricia F.

doi:10.1093/cercor/bhy004

Cited by 28 publications

(115 citation statements)

References 84 publications

(119 reference statements)

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“…While ADAM10 cKO mice have a reduced number of dendritic spines (Prox et al , ), NrCAM KO mice have increased dendritic spine densities. Together with Neuropilin‐2 and Plexin A3, NrCAM is part of a Sema3F receptor complex, which is mediating a Sema3F‐induced spine retraction (Demyanenko et al , ; Mohan et al , ). Thus, increased NrCAM surface levels, as we observed upon inhibition of ADAM10, would be expected to decrease spine density, as reported for ADAM10 cKO mice.…”

Section: Discussionmentioning

confidence: 99%

Nr CAM is a marker for substrate‐selective activation of ADAM 10 in Alzheimer's disease

et al. 2019

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The metalloprotease ADAM 10 is a drug target in Alzheimer's disease, where it cleaves the amyloid precursor protein ( APP ) and lowers amyloid‐beta. Yet, ADAM 10 has additional substrates, which may cause mechanism‐based side effects upon therapeutic ADAM 10 activation. However, they may also serve—in addition to APP —as biomarkers to monitor ADAM 10 activity in patients and to develop APP ‐selective ADAM 10 activators. Our study demonstrates that one such substrate is the neuronal cell adhesion protein Nr CAM . ADAM 10 controlled Nr CAM surface levels and regulated neurite outgrowth in vitro in an Nr CAM ‐dependent manner. However, ADAM 10 cleavage of Nr CAM , in contrast to APP , was not stimulated by the ADAM 10 activator acitretin, suggesting that substrate‐selective ADAM 10 activation may be feasible. Indeed, a whole proteome analysis of human CSF from a phase II clinical trial showed that acitretin, which enhanced APP cleavage by ADAM 10, spared most other ADAM 10 substrates in brain, including Nr CAM . Taken together, this study demonstrates an Nr CAM ‐dependent function for ADAM 10 in neurite outgrowth and reveals that a substrate‐selective, therapeutic ADAM 10 activation is possible and may be monitored with Nr CAM .

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Section: Discussionmentioning

confidence: 99%

Nr CAM is a marker for substrate‐selective activation of ADAM 10 in Alzheimer's disease

et al. 2019

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“…The antibody does not react with other L1-CAMs in mouse brain or transfected HEK293 cells and does not bind nonspecifically to CHL1-null mutant mouse brain (Nikonenko et al, 2006). The NrCAM antibody, also directed against the extracellular region, does not cross-react with other L1-CAMs, as previously characterized (Demyanenko et al, 2011b(Demyanenko et al, , 2014Mohan et al, 2019). The Sema3B antibody was generated against a synthetic peptide (human Sema3B residues 100 -200 in the Sema domain) and reacts specifically with mouse or human Sema3B, not with Sema3F (Nguyen et al, 2011).…”

Section: Methodsmentioning

confidence: 56%

“…The ability of L1-CAMs and Sema3s to promote axon repulsion, taken together with their robust expression in the postnatal neocortex, suggested that they might also have a repellent function in cortical pyramidal neurons. Consistent with this hypothesis, Sema3F induces spine retraction in cortical pyramidal neurons (Tran et al, 2009), and NrCAM serves as a functional subunit of the Sema3F receptor complex to limit the density of spine subpopulations in the prefrontal cortex (PFC) and primary visual cortex (V1) (Tran et al, 2009;Demyanenko et al, 2014;Mohan et al, 2019).…”

Section: Introductionmentioning

confidence: 74%

“…CHL1 mutant mice display no obvious neuroanatomical abnormalities but have aberrant hippocampal mossy fiber and olfactory sensory axon projections (Montag-Sallaz et al, 2003), as well as thalamocortical targeting defects (Wright et al, 2007;Demyanenko et al, 2011a). NexCre-ERT2 mice (C57BL/6J) (Agarwal et al, 2012) were crossed to the Ai9 reporter line Rosa-CAG-(LoxP-Stop-LoxP-tdTomato)-WPRE (C57BL/6) (Madisen et al, 2010) and treated with tamoxifen from P10-P13 to induce recombination in postmitotic, postmigratory pyramidal neurons as described previously (Mohan et al, 2019). Mice were maintained in the University of North Carolina Animal Facility and handled according to Institutional Animal Care and Use Committee policies in accordance with National Institutes of Health guidelines.…”

Section: Methodsmentioning

confidence: 99%

“…Cortical neuron cultures from E15.5 mouse embryos were transfected on DIV11 with pCAGG-IRES-mEGFP and then treated at DIV14 with Fc-fusion proteins (5 nM) for 30 min, as described previously (Demyanenko et al, 2014). After fixation and immunostaining for EGFP, spine density was quantified on apical dendrites of neurons with pyramidal morphology in confocal z-stacks using Neurolucida software (Tran et al, 2009;Demyanenko et al, 2014;Mohan et al, 2019). Sema3B-Fc was found to induce a 40% decrease in spine density on apical dendrites compared with control Fc protein, whereas Sema3F-Fc caused an 81% decrease ( Fig.…”

Section: Regulation Of Sema3b-induced Spine Retraction By Chl1mentioning

confidence: 99%

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Close Homolog of L1 Regulates Dendritic Spine Density in the Mouse Cerebral Cortex Through Semaphorin 3B

et al. 2019

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Dendritic spines in the developing mammalian neocortex are initially overproduced and then eliminated during adolescence to achieve appropriate levels of excitation in mature networks. We show here that the L1 family cell adhesion molecule Close Homolog of L1 (CHL1) and secreted repellent ligand Semaphorin 3B (Sema3B) function together to induce dendritic spine pruning in developing cortical pyramidal neurons. Loss of CHL1 in null mutant mice in both genders resulted in increased spine density and a greater proportion of immature spines on apical dendrites in the prefrontal and visual cortex. Electron microscopy showed that excitatory spine synapses with postsynaptic densities were increased in the CHL1-null cortex, and electrophysiological recording in prefrontal slices from mutant mice revealed deficiencies in excitatory synaptic transmission. Mechanistically, Sema3B protein induced elimination of spines on apical dendrites of cortical neurons cultured from wild-type but not CHL1-null embryos. Sema3B was secreted by the cortical neuron cultures, and its levels increased when cells were treated with the GABA antagonist gabazine. In vivo CHL1 was coexpressed with Sema3B in pyramidal neuron subpopulations and formed a complex with Sema3B receptor subunits Neuropilin-2 and PlexinA4. CHL1 and NrCAM, a closely related L1 adhesion molecule, localized primarily to distinct spines and promoted spine elimination to Sema3B or Sema3F, respectively. These results support a new concept in which selective spine elimination is achieved through different secreted semaphorins and L1 family adhesion molecules to sculpt functional neural circuits during postnatal maturation. Significance StatementDendritic spines in the mammalian neocortex are initially overproduced and then pruned in adolescent life through unclear mechanisms to sculpt maturing cortical circuits. Here, we show that spine and excitatory synapse density of pyramidal neurons in the developing neocortex is regulated by the L1 adhesion molecule, Close Homolog of L1 (CHL1). CHL1 mediated spine pruning in response to the secreted repellent ligand Semaphorin 3B and associated with receptor subunits Neuropilin-2 and PlexinA4. CHL1 and related L1 adhesion molecule NrCAM localized to distinct spines, and promoted spine elimination to Semaphorin 3B and -3F, respectively. These results support a new concept in which selective elimination of individual spines and nascent synapses can be achieved through the action of distinct secreted semaphorins and L1 adhesion molecules.

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Neuropsychopathology of Autism Spectrum Disorder: Complex Interplay of Genetic, Epigenetic, and Environmental Factors

Bhandari

Paliwal

Kuhad

2020

Advances in Neurobiology

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Temporal Regulation of Dendritic Spines Through NrCAM-Semaphorin3F Receptor Signaling in Developing Cortical Pyramidal Neurons

Cited by 28 publications

References 84 publications

Nr CAM is a marker for substrate‐selective activation of ADAM 10 in Alzheimer's disease

Nr CAM is a marker for substrate‐selective activation of ADAM 10 in Alzheimer's disease

Close Homolog of L1 Regulates Dendritic Spine Density in the Mouse Cerebral Cortex Through Semaphorin 3B

Neuropsychopathology of Autism Spectrum Disorder: Complex Interplay of Genetic, Epigenetic, and Environmental Factors

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