scholarly journals Role of Numb in Dendritic Spine Development with a Cdc42 GEF Intersectin and EphB2

2006 ◽  
Vol 17 (3) ◽  
pp. 1273-1285 ◽  
Author(s):  
Takashi Nishimura ◽  
Tomoya Yamaguchi ◽  
Akinori Tokunaga ◽  
Akitoshi Hara ◽  
Tomonari Hamaguchi ◽  
...  
Keyword(s):  
Dendritic Spine ◽  
Hippocampal Neurons ◽  
Neuronal Development ◽  
System Development ◽  
Direct Interaction ◽  
Nervous System Development ◽  
Nucleotide Exchange ◽  
Spine Development

Numb has been implicated in cortical neurogenesis during nervous system development, as a result of its asymmetric partitioning and antagonizing Notch signaling. Recent studies have revealed that Numb functions in clathrin-dependent endocytosis by binding to the AP-2 complex. Numb is also expressed in postmitotic neurons and plays a role in axonal growth. However, the functions of Numb in later stages of neuronal development remain unknown. Here, we report that Numb specifically localizes to dendritic spines in cultured hippocampal neurons and is implicated in dendritic spine morphogenesis, partially through the direct interaction with intersectin, a Cdc42 guanine nucleotide exchange factor (GEF). Intersectin functions as a multidomain adaptor for proteins involved in endocytosis and cytoskeletal regulation. Numb enhanced the GEF activity of intersectin toward Cdc42 in vivo. Expression of Numb or intersectin caused the elongation of spine neck, whereas knockdown of Numb and Numb-like decreased the protrusion density and its length. Furthermore, Numb formed a complex with EphB2 receptor-type tyrosine kinase and NMDA-type glutamate receptors. Knockdown of Numb suppressed the ephrin-B1-induced spine development and maturation. These results highlight a role of Numb for dendritic spine development and synaptic functions with intersectin and EphB2.

scholarly journals Rac GEF Dock4 interacts with cortactin to regulate dendritic spine formation

2013 ◽  
Vol 24 (10) ◽  
pp. 1602-1613 ◽  
Author(s):  
Shuhei Ueda ◽  
Manabu Negishi ◽  
Hironori Katoh
Keyword(s):  
Dendritic Spine ◽  
Hippocampal Neurons ◽  
Molecular Mechanisms ◽  
Neuronal Development ◽  
Actin Binding ◽  
Spine Density ◽  
Nucleotide Exchange ◽  
Spine Formation ◽  
Nucleotide Exchange Factor ◽  
Important Interaction

In neuronal development, dendritic spine formation is important for the establishment of excitatory synaptic connectivity and functional neural circuits. Developmental deficiency in spine formation results in multiple neuropsychiatric disorders. Dock4, a guanine nucleotide exchange factor (GEF) for Rac, has been reported as a candidate genetic risk factor for autism, dyslexia, and schizophrenia. We previously showed that Dock4 is expressed in hippocampal neurons. However, the functions of Dock4 in hippocampal neurons and the underlying molecular mechanisms are poorly understood. Here we show that Dock4 is highly concentrated in dendritic spines and implicated in spine formation via interaction with the actin-binding protein cortactin. In cultured neurons, short hairpin RNA (shRNA)–mediated knockdown of Dock4 reduces dendritic spine density, which is rescued by coexpression of shRNA-resistant wild-type Dock4 but not by a GEF-deficient mutant of Dock4 or a truncated mutant lacking the cortactin-binding region. On the other hand, knockdown of cortactin suppresses Dock4-mediated spine formation. Taken together, the results show a novel and functionally important interaction between Dock4 and cortactin for regulating dendritic spine formation via activation of Rac.

scholarly journals Dpysl2 (CRMP2) is required for the migration of facial branchiomotor neurons in the developing zebrafish embryo

2020 ◽  
Vol 64 (10-11-12) ◽  
pp. 479-484
Author(s):  
Carolina Fiallos-Oliveros ◽  
Toshio Ohshima
Keyword(s):  
Motor Neurons ◽  
System Development ◽  
Nervous System Development ◽  
Knock Out ◽  
Facial Branchiomotor Neurons ◽  
Morpholino Oligonucleotides ◽  
Mutant Phenotypes ◽  
Antisense Morpholino Oligonucleotides

Dihydropyrimidinase-like family proteins (Dpysls) are relevant in several processes during nervous system development; among others, they are involved in axonal growth and cell migration. Dpysl2 (CRMP2) is the most studied member of this family; however, its role in vivo is still being investigated. Our previous studies in zebrafish showed the requirement of Dpysl2 for the proper positioning of caudal primary motor neurons and Rohon-Beard neurons in the spinal cord.In the present study, we show that Dpysl2 is necessary for the proper migration of facial branchiomotor neurons during early development in zebrafish. We generated a dpysl2 knock-out (KO) zebrafish mutant line and used different types of antisense morpholino oligonucleotides (AMO) to analyze the role of Dpysl2 in this process. Both dpysl2 KO mutants and morphants exhibited abnormalities in the migration of these neurons from rhombomers (r) 4 and 5 to 6 and 7. The facial branchiomotor neurons that were expected to be at r6 were still located at r4 and r5 hours after the migration process should have been completed. In addition, mutant phenotypes were rescued by injecting dpysl2 mRNA into the KO embryos. These results indicate that Dpysl2 is involved in the proper migration of facial branchiomotor neurons in developing zebrafish embryos.

scholarly journals Met is required for oligodendrocyte progenitor cell migration in Danio rerio

2021 ◽  
Author(s):  
Authors: Maria F Ali ◽  
Andrew J Latimer ◽  
Yinxue Wang ◽  
Leah Hogenmiller ◽  
Laura Fontenas ◽  
...  
Keyword(s):  
System Development ◽  
Nervous System Development ◽  
Oligodendrocyte Progenitor Cells ◽  
Oligodendrocyte Progenitor ◽  
Overlapping Domains ◽  
Insight Into ◽  
Ventral Spinal Cord ◽  
Vertebrate Central Nervous System

Abstract During vertebrate central nervous system development, most oligodendrocyte progenitor cells (OPCs) are specified in the ventral spinal cord and must migrate throughout the neural tube until they become evenly distributed, occupying non-overlapping domains. While this process of developmental OPC migration is well characterized, the nature of the molecular mediators that govern it remain largely unknown. Here, using zebrafish as a model, we demonstrate that Met signaling is required for initial developmental migration of OPCs, and, using cell-specific knock-down of Met signaling, show that Met acts cell-autonomously in OPCs. Taken together, these findings demonstrate in vivo, the role of Met signaling in OPC migration and provide new insight into how OPC migration is regulated during development.

scholarly journals Neuronal actin dynamics, spine density and neuronal dendritic complexity are regulated by CAP2

2015 ◽  
Author(s):  
Atul Kumar ◽  
Lars Paeger ◽  
Kosmas Kosmas ◽  
Peter Kloppenburg ◽  
Angelika Noegel ◽  
...  
Keyword(s):  
Dendritic Spine ◽  
Neuronal Development ◽  
Actin Dynamics ◽  
Spine Density ◽  
Delayed Wound Healing ◽  
Actin Remodeling ◽  
Cardiovascular Defects ◽  
Dendritic Complexity

Actin remodeling is indispensable for dendritic spine development, morphology and density which signify learning, memory and motor skills. CAP2 is a regulator of actin dynamics through sequestering G-actin and severing F-actin. In a mouse model, ablation of CAP2 leads to cardiovascular defects and delayed wound healing. This report investigates the role of CAP2 in the brain using Cap2gt/gt mice. Dendritic spine density and neuronal dendritic length were altered in Cap2gt/gt. This was accompanied by increased F-actin content and F-actin accumulation in cultured Cap2gt/gt neurons. In membrane depolarization assays, Cap2gt/gt synaptosomes exhibit an impaired F/G actin ratio, indicating altered actin dynamics. We show an interaction between CAP2 and n-cofilin, presumably mediated through the C-terminal domain of CAP2 and is cofilin ser3 phosphorylation dependent. In vivo, the consequences of this interaction were altered phosphorylated cofilin levels and formation of cofilin aggregates in the neurons. Thus, our studies identify a novel role of CAP2 in neuronal development and neuronal actin dynamics.

scholarly journals Phosphorylation of CRMP2 by Cdk5 Regulates Dendritic Spine Development of Cortical Neuron in the Mouse Hippocampus

2016 ◽  
Vol 2016 ◽  
pp. 1-7 ◽  
Author(s):  
Xiaohua Jin ◽  
Kodai Sasamoto ◽  
Jun Nagai ◽  
Yuki Yamazaki ◽  
Kenta Saito ◽  
...  
Keyword(s):  
Mouse Brain ◽  
Dendritic Spines ◽  
Dendritic Spine ◽  
Cortical Neurons ◽  
Hippocampal Neurons ◽  
Molecular Mechanisms ◽  
Brain Functions ◽  
Spine Development ◽  
Mouse Hippocampus

Proper density and morphology of dendritic spines are important for higher brain functions such as learning and memory. However, our knowledge about molecular mechanisms that regulate the　development and maintenance of dendritic spines is limited. We recently reported that cyclin-dependent kinase 5 (Cdk5) is required for the development and maintenance of dendritic spines of cortical neurons in the mouse brain. Previousin vitrostudies have suggested the involvement of Cdk5 substrates in the formation of dendritic spines; however, their role in spine development has not been testedin vivo. Here, we demonstrate that Cdk5 phosphorylates collapsin response mediator protein 2 (CRMP2) in the dendritic spines of cultured hippocampal neurons andin vivoin the mouse brain. When we eliminated CRMP2 phosphorylation inCRMP2KI/KImice, the densities of dendritic spines significantly decreased in hippocampal CA1 pyramidal neurons in the mouse brain. These results indicate that phosphorylation of CRMP2 by Cdk5 is important for dendritic spine development in cortical neurons in the mouse hippocampus.

NF-κB-c-REL impairment drives human stem cells into the oligodendroglial fate

2019 ◽  
Author(s):  
Lucia M Ruiz-Perera ◽  
Johannes FW Greiner ◽  
Christian Kaltschmidt ◽  
Barbara Kaltschmidt
Keyword(s):  
Stem Cells ◽  
Neuronal Differentiation ◽  
Molecular Mechanisms ◽  
Neuronal Development ◽  
System Development ◽  
Nervous System Development ◽  
Human Stem Cells ◽  
Human Neural Stem Cells ◽  
Transcription Factor Nuclear Factor

AbstractMolecular mechanisms underlying fate decisions of human neural stem cells (NSCs) between neurogenesis and gliogenesis are critical during neuronal development and progression of neurodegenerative diseases. Despite its crucial role in murine nervous system development, the potential role of the transcription factor nuclear factor kappa-light-chain-enhancer of activated B-cells (NF-κB) in fate shifts of human stem cells is poorly understood.Facing this challenge, we demonstrate here that NF-κB-c-REL drives glutamatergic differentiation of adult human stem cells, while its impairment results in a shift towards the oligodendroglial fate. We particularly observed an opposing balance switch from NF-κB-RELB/p52 to NF-κB-c-REL during early neuronal differentiation of NSCs originating from neural crest-derived stem cells. Exposure of differentiating human NSCs to the c-REL inhibiting approved drug pentoxifylline (PTXF) resulted in elevated levels of cell death and significantly decreased amounts of NF200+/VGLUT2+ neurons. PTXF-mediated inhibition of c-REL further drove human NSCs into the oligodendrocyte fate, as demonstrated by a complete switch to OLIG2+/O4+ oligodendrocytes, which also showed PDGFRα, NG2 and MBP transcripts.In summary, we present here a novel human cellular model of neuronal differentiation with an essential role of NF-κB-c-REL in fate choice between neurogenesis and oligodendrogenesis potentially relevant for multiple sclerosis and schizophrenia.

scholarly journals Role of kinesin-1–based microtubule sliding in Drosophila nervous system development

2016 ◽  
Vol 113 (34) ◽  
pp. E4985-E4994 ◽  
Author(s):  
Michael Winding ◽  
Michael T. Kelliher ◽  
Wen Lu ◽  
Jill Wildonger ◽  
Vladimir I. Gelfand
Keyword(s):  
Nervous System ◽  
Binding Site ◽  
Heavy Chain ◽  
System Development ◽  
Nervous System Development ◽  
Axon Outgrowth ◽  
Organelle Transport ◽  
Genomic Locus

The plus-end microtubule (MT) motor kinesin-1 is essential for normal development, with key roles in the nervous system. Kinesin-1 drives axonal transport of membrane cargoes to fulfill the metabolic needs of neurons and maintain synapses. We have previously demonstrated that kinesin-1, in addition to its well-established role in organelle transport, can drive MT–MT sliding by transporting “cargo” MTs along “track” MTs, resulting in dramatic cell shape changes. The mechanism and physiological relevance of this MT sliding are unclear. In addition to its motor domain, kinesin-1 contains a second MT-binding site, located at the C terminus of the heavy chain. Here, we mutated this C-terminal MT-binding site such that the ability of kinesin-1 to slide MTs is significantly compromised, whereas cargo transport is unaffected. We introduced this mutation into the genomic locus of kinesin-1 heavy chain (KHC), generating the KhcmutA allele. KhcmutA neurons displayed significant MT sliding defects while maintaining normal transport of many cargoes. Using this mutant, we demonstrated that MT sliding is required for axon and dendrite outgrowth in vivo. Consistent with these results, KhcmutA flies displayed severe locomotion and viability defects. To test the role of MT sliding further, we engineered a chimeric motor that actively slides MTs but cannot transport organelles. Activation of MT sliding in KhcmutA neurons using this chimeric motor rescued axon outgrowth in cultured neurons and in vivo, firmly establishing the role of sliding in axon outgrowth. These results demonstrate that MT sliding by kinesin-1 is an essential biological phenomenon required for neuronal morphogenesis and normal nervous system development.

scholarly journals Met is required for oligodendrocyte progenitor cell migration in Danio rerio

2021 ◽  
Author(s):  
Maria F Ali ◽  
Andrew J Latimer ◽  
Yinxue Wang ◽  
Leah Hogenmiller ◽  
Laura Fontenas ◽  
...  
Keyword(s):  
System Development ◽  
Nervous System Development ◽  
Oligodendrocyte Progenitor Cells ◽  
Oligodendrocyte Progenitor ◽  
Overlapping Domains ◽  
Insight Into ◽  
Ventral Spinal Cord ◽  
Vertebrate Central Nervous System

During vertebrate central nervous system development, most oligodendrocyte progenitor cells (OPCs) are specified in the ventral spinal cord and must migrate throughout the neural tube until they become evenly distributed, occupying non-overlapping domains. While this process of developmental OPC migration is well characterized, the nature of the molecular mediators that govern it remain largely unknown. Here, using zebrafish as a model, we demonstrate that Met signaling is required for initial developmental migration of OPCs, and, using cell-specific knock-down of Met signaling, show that Met acts cell-autonomously in OPCs. Taken together, these findings demonstrate in vivo, the role of Met signaling in OPC migration and provide new insight into how OPC migration is regulated during development.

scholarly journals Zebrafish Models of Autosomal Recessive Ataxias

Cells ◽  
2021 ◽  
Vol 10 (4) ◽  
pp. 836
Author(s):  
Ana Quelle-Regaldie ◽  
Daniel Sobrido-Cameán ◽  
Antón Barreiro-Iglesias ◽  
María Jesús Sobrido ◽  
Laura Sánchez
Keyword(s):  
Animal Models ◽  
Autosomal Recessive ◽  
Molecular Mechanisms ◽  
System Development ◽  
Rapid Development ◽  
Nervous System Development ◽  
Central Nervous System Development ◽  
Cellular Processes ◽  
Recessive Disorders

Autosomal recessive ataxias are much less well studied than autosomal dominant ataxias and there are no clearly defined systems to classify them. Autosomal recessive ataxias, which are characterized by neuronal and multisystemic features, have significant overlapping symptoms with other complex multisystemic recessive disorders. The generation of animal models of neurodegenerative disorders increases our knowledge of their cellular and molecular mechanisms and helps in the search for new therapies. Among animal models, the zebrafish, which shares 70% of its genome with humans, offer the advantages of being small in size and demonstrating rapid development, making them optimal for high throughput drug and genetic screening. Furthermore, embryo and larval transparency allows to visualize cellular processes and central nervous system development in vivo. In this review, we discuss the contributions of zebrafish models to the study of autosomal recessive ataxias characteristic phenotypes, behavior, and gene function, in addition to commenting on possible treatments found in these models. Most of the zebrafish models generated to date recapitulate the main features of recessive ataxias.

scholarly journals Drosophila Stathmin: A Microtubule-destabilizing Factor Involved in Nervous System Formation

2002 ◽  
Vol 13 (2) ◽  
pp. 698-710 ◽  
Author(s):  
Sylvie Ozon ◽  
Antoine Guichet ◽  
Olivier Gavet ◽  
Siegfried Roth ◽  
André Sobel
Keyword(s):  
Nervous System ◽  
System Development ◽  
Nervous System Development ◽  
Microtubule Assembly ◽  
Nervous Systems ◽  
Germ Cell Migration ◽  
Numerous Cell ◽  
First Time

Stathmin is a ubiquitous regulatory phosphoprotein, the generic element of a family of neural phosphoproteins in vertebrates that possess the capacity to bind tubulin and interfere with microtubule dynamics. Although stathmin and the other proteins of the family have been associated with numerous cell regulations, their biological roles remain elusive, as in particular inactivation of the stathmin gene in the mouse resulted in no clear deleterious phenotype. We identified stathmin phosphoproteins inDrosophila, encoded by a unique gene sharing the intron/exon structure of the vertebrate stathmin andstathmin family genes. They interfere with microtubule assembly in vitro, and in vivo when expressed in HeLa cells. Drosophila stathmin expression is regulated during embryogenesis: it is high in the migrating germ cells and in the central and peripheral nervous systems, a pattern resembling that of mammalian stathmin. Furthermore, RNA interference inactivation ofDrosophila stathmin expression resulted in germ cell migration arrest at stage 14. It also induced important anomalies in nervous system development, such as loss of commissures and longitudinal connectives in the ventral cord, or abnormal chordotonal neuron organization. In conclusion, a single Drosophilagene encodes phosphoproteins homologous to the entire vertebrate stathmin family. We demonstrate for the first time their direct involvement in major biological processes such as development of the reproductive and nervous systems.

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