Autocrine Action of BDNF on Dendrite Development of Adult-Born Hippocampal Neurons

AbstractMutations of the X-linked methyl-CpG-binding protein 2 (MECP2) gene in humans are responsible for most cases of Rett syndrome (RTT), an X-linked progressive neurological disorder. While genome-wide screens in clinical trials reveal several putative RTT-associated mutations on MECP2, their causative relevance regarding the functional regulation of MeCP2 on the etiologic sites at the protein level require more evidence. In this study, we demonstrate that MeCP2 is dynamically modified by O-linked-β-N-acetylglucosamine (O-GlcNAc) at threonine 203 (T203), an etiologic site in RTT patients. Disruption of the O-GlcNAcylation of MeCP2 specifically at T203 impairs dendrite development and spine maturation in cultured hippocampal neurons, and disrupts neuronal migration, dendritic spine morphogenesis and dysfunction of synaptic transmission in the developing and juvenile mouse cerebral cortex. Mechanistically, genetic disruption of O-GlcNAcylation at T203 on MeCP2 decreases neuronal activity-induced induction of Bdnf transcription. Our study highlights the critical role of MeCP2 T203 O-GlcNAcylation in neural development and synaptic transmission potentially via BDNF.

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The Signaling Adaptor Protein CD3ζ Is a Negative Regulator of Dendrite Development in Young Neurons

Molecular Biology of the Cell ◽

10.1091/mbc.e07-09-0947 ◽

2008 ◽

Vol 19 (6) ◽

pp. 2444-2456 ◽

Cited By ~ 23

Author(s):

Stéphane J. Baudouin ◽

Julie Angibaud ◽

Gildas Loussouarn ◽

Virginie Bonnamain ◽

Akihiro Matsuura ◽

...

Keyword(s):

Hippocampal Neurons ◽

Neuronal Development ◽

Adaptor Protein ◽

Neurite Growth ◽

Negative Regulator ◽

Cultured Neurons ◽

Loss Of Function ◽

Dendrite Development ◽

Neuronal Functions ◽

Immunohistochemical Analyses

A novel idea is emergxsing that a large molecular repertoire is common to the nervous and immune systems, which might reflect the existence of novel neuronal functions for immune molecules in the brain. Here, we show that the transmembrane adaptor signaling protein CD3ζ, first described in the immune system, has a previously uncharacterized role in regulating neuronal development. Biochemical and immunohistochemical analyses of the rat brain and cultured neurons showed that CD3ζ is mainly expressed in neurons. Distribution of CD3ζ in developing cultured hippocampal neurons, as determined by immunofluorescence, indicates that CD3ζ is preferentially associated with the somatodendritic compartment as soon as the dendrites initiate their differentiation. At this stage, CD3ζ was selectively concentrated at dendritic filopodia and growth cones, actin-rich structures involved in neurite growth and patterning. siRNA-mediated knockdown of CD3ζ in cultured neurons or overexpression of a loss-of-function CD3ζ mutant lacking the tyrosine phosphorylation sites in the immunoreceptor tyrosine-based activation motifs (ITAMs) increased dendritic arborization. Conversely, activation of endogenous CD3ζ by a CD3ζ antibody reduced the size of the dendritic arbor. Altogether, our findings reveal a novel role for CD3ζ in the nervous system, suggesting its contribution to dendrite development through ITAM-based mechanisms.

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Reelin Affects Signaling Pathways of a Group of Inhibitory Neurons and the Development of Inhibitory Synapses in Primary Neurons

International Journal of Molecular Sciences ◽

10.3390/ijms22147510 ◽

2021 ◽

Vol 22 (14) ◽

pp. 7510

Author(s):

Gum Hwa Lee ◽

Seong-Eun Lee

Keyword(s):

Hippocampal Neurons ◽

Secretory Protein ◽

Protein Supplementation ◽

Inhibitory Neurons ◽

Inhibitory Synapses ◽

Cellular Mechanisms ◽

Dendrite Development ◽

Excitatory Neurons ◽

And Function

Reelin is a secretory protein involved in a variety of processes in forebrain development and function, including neuronal migration, dendrite growth, spine formation, and synaptic plasticity. Most of the function of Reelin is focused on excitatory neurons; however, little is known about its effects on inhibitory neurons and inhibitory synapses. In this study, we investigated the phosphatidylinositol 3-kinase/Akt pathway of Reelin in primary cortical and hippocampal neurons. Individual neurons were visualized using immunofluorescence to distinguish inhibitory neurons from excitatory neurons. Reelin-rich protein supplementation significantly induced the phosphorylation of Akt and ribosomal S6 protein in excitatory neurons, but not in most inhibitory neurons. In somatostatin-expressing inhibitory neurons, one of major subtypes of inhibitory neurons, Reelin-rich protein supplementation induced the phosphorylation of S6. Subsequently, we investigated whether or not Reelin-rich protein supplementation affected dendrite development in cultured inhibitory neurons. Reelin-rich protein supplementation did not change the total length of dendrites in inhibitory neurons in vitro. Finally, we examined the development of inhibitory synapses in primary hippocampal neurons and found that Reelin-rich protein supplementation significantly reduced the density of gephyrin–VGAT-positive clusters in the dendritic regions without changing the expression levels of several inhibitory synapse-related proteins. These findings indicate a new role for Reelin in specific groups of inhibitory neurons and the development of inhibitory synapses, which may contribute to the underlying cellular mechanisms of RELN-associated neurological disorders.

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