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.

Rapid Effects of Estradiol on Dendritic Spines and Synaptic Plasticity in the Male and Female Hippocampus

2020 ◽  
pp. 38-47
Author(s):  
Asami Kato ◽  
Gen Murakami ◽  
Yasushi Hojo ◽  
Sigeo Horie ◽  
Suguru Kawato
Keyword(s):  
Synaptic Plasticity ◽  
Dendritic Spine ◽  
Hippocampal Neurons ◽  
Molecular Mechanisms ◽  
Hippocampal Slices ◽  
Spine Density ◽  
Male And Female ◽  
Dendritic Spine Density ◽  
Male And Female Rats ◽  
Rapid Modulation

Although the potent estrogen, 17β‎-estradiol (E2), has long been known to regulate the hippocampal dendritic spine density and synaptic plasticity, the molecular mechanisms through which it does so are less well understood. This chapter discusses the rapid modulation of hippocampal dendritic spine density and synaptic plasticity in male and female rats, with particular attention to studies in hippocampal slices from male rats. Among the mechanisms described are the roles of specific cell-signaling kinases and estrogen receptors in mediating the effects of E2 and progesterone on hippocampal neurons. In addition, dynamic changes of spine structures over time and sex differences in spine regulation are also considered. Finally, the chapter ends by discussing the importance of local hippocampal synthesis of E2 and androgens to hippocampal spine morphology and plasticity.

scholarly journals GEFT, A Rho Family Guanine Nucleotide Exchange Factor, Regulates Neurite Outgrowth and Dendritic Spine Formation

2004 ◽  
Vol 279 (44) ◽  
pp. 45824-45832 ◽  
Author(s):  
Brad Bryan ◽  
Vikas Kumar ◽  
Lewis Joe Stafford ◽  
Yi Cai ◽  
Gangyi Wu ◽  
...  
Keyword(s):  
Neurite Outgrowth ◽  
Dendritic Spine ◽  
Neuroblastoma Cells ◽  
Guanine Nucleotide Exchange Factor ◽  
Guanine Nucleotide ◽  
Nucleotide Exchange ◽  
Spine Formation ◽  
Guanine Nucleotide Exchange ◽  
Nucleotide Exchange Factor ◽  
Rho Family

The Rho family of small GTPases controls a wide range of cellular processes in eukaryotic cells, such as normal cell growth, proliferation, differentiation, gene regulation, actin cytoskeletal organization, cell fate determination, and neurite outgrowth. The activation of Rho-GTPases requires the exchange of GDP for GTP, a process catalyzed by the Dbl family of guanine nucleotide exchange factors. We demonstrate that a newly identified guanine nucleotide exchange factor, GEFT, is widely expressed in the brain and highly concentrated in the hippocampus, and the Purkinje and granular cells of the cerebellum. Exogenous expression of GEFT promotes dendrite outgrowth in hippocampal neurons, resulting in spines with larger size as compared with control spines. In neuroblastoma cells, GEFT promotes the active GTP-bound state of Rac1, Cdc42, and RhoA and increases neurite outgrowth primarily via Rac1. Furthermore, we demonstrated that PAK1 and PAK5, both downstream effectors of Rac1/Cdc42, are necessary for GEFT-induced neurite outgrowth. AP-1 and NF-κB, two transcriptional factors involved in neurite outgrowth and survival, were up-regulated in GEFT-expressing cells. Together, our data suggest that GEFT enhances dendritic spine formation and neurite outgrowth in primary neurons and neuroblastoma cells, respectively, through the activation of Rac/Cdc42-PAK signaling pathways.

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 Autism-linked mutations of CTTNBP2 reduce social interaction and impair dendritic spine formation via diverse mechanisms

2020 ◽  
Vol 8 (1) ◽  
Author(s):  
Pu-Yun Shih ◽  
Bing-Yuan Hsieh ◽  
Ching-Yen Tsai ◽  
Chiu-An Lo ◽  
Brian E. Chen ◽  
...  
Keyword(s):  
Social Interaction ◽  
Dendritic Spine ◽  
Hippocampal Neurons ◽  
Short Form ◽  
Autism Spectrum ◽  
Synaptic Function ◽  
Synaptic Proteins ◽  
Spine Density ◽  
Spine Formation ◽  
Molecular Features

Abstract Abnormal synaptic formation and signaling is one of the key molecular features of autism spectrum disorders (ASD). Cortactin binding protein 2 (CTTNBP2), an ASD-linked gene, is known to regulate the subcellular distribution of synaptic proteins, such as cortactin, thereby controlling dendritic spine formation and maintenance. However, it remains unclear how ASD-linked mutations of CTTNBP2 influence its function. Here, using cultured hippocampal neurons and knockin mouse models, we screen seven ASD-linked mutations in the short form of the Cttnbp2 gene and identify that M120I, R533* and D570Y mutations impair CTTNBP2 protein–protein interactions via divergent mechanisms to reduce dendritic spine density in neurons. R533* mutation impairs CTTNBP2 interaction with cortactin due to lack of the C-terminal proline-rich domain. Through an N–C terminal interaction, M120I mutation at the N-terminal region of CTTNBP2 also negatively influences cortactin interaction. D570Y mutation increases the association of CTTNBP2 with microtubule, resulting in a dendritic localization of CTTNBP2, consequently reducing the distribution of CTTNBP2 in dendritic spines and impairing the synaptic function of CTTNBP2. Finally, we generated heterozygous M120I knockin mice to mimic the genetic variation of patients and found they exhibit reduced social interaction. Our study elucidates that different ASD-linked mutations of CTTNBP2 result in diverse molecular deficits, but all have the similar consequence of synaptic impairment.

scholarly journals Estradiol Increases Dendritic Spine Density by Reducing GABA Neurotransmission in Hippocampal Neurons

1998 ◽  
Vol 18 (7) ◽  
pp. 2550-2559 ◽  
Author(s):  
Diane D. Murphy ◽  
Nelson B. Cole ◽  
V. Greenberger ◽  
Menahem Segal
Keyword(s):  
Dendritic Spine ◽  
Hippocampal Neurons ◽  
Spine Density ◽  
Dendritic Spine Density ◽  
Gaba Neurotransmission
Sign in / Sign up

Export Citation Format

Share Document