The Atypical Guanine-Nucleotide Exchange Factor, Dock7, Negatively Regulates Schwann Cell Differentiation and Myelination

Yamauchi, Junji; Miyamoto, Yuki; Hamasaki, Hajime; Sanbe, Atsushi; Kusakawa, Shinji; Nakamura, Akinori; Tsumura, Hideki; Maeda, Masahiro; Nemoto, Noriko; Kawahara, Katsumasa; Torii, Tomohiro; Tanoue, Akito

doi:10.1523/jneurosci.2738-11.2011

Cited by 41 publications

(43 citation statements)

References 63 publications

(131 reference statements)

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“…Genetically modified/unmodified mice were cared for in accordance with a protocol approved by the Japanese National [8,14]. Transgenic founders were mated to wild type C57BL/6JJmc and the transgene was stably maintained for at least 10 generations.…”

Section: Generation and Identification Of Shdock7 Transgenic Micementioning

confidence: 99%

“…~200,000 SCs were seeded onto purified DRG neuronal cultures (~70,000 cells). SCneuronal cocultures were maintained in MEM containing 10% FBS and 100 ng/ml NGF [8]. Axonal processes and endogenous Schwann cells were allowed to grow and establish themselves for 5 days.…”

Section: Cultures Of Primary Cells and In Vitro Myelinationmentioning

confidence: 99%

“…In primary SCs (Figure 2(a)) and sciatic nerves (Figure 2(b)) from Dock7 shRNA transgenic mice, Dock7 was effectively knocked down, as revealed by immunoblotting with an antibody specific for Dock7. Thus, we succeeded in generating novel Dock7 shRNA transgenic mice in which the transgene position differs from that of previously-characterized transgenic mice [8]. These transgenic mice, as well as heir nontransgenic littermates, appeared healthy over t effect on myelin formation in vivo, we analyzed sciatic nerve cross sections using electron microscopy.…”

Section: Newly-generated Dock7 Shrna Transgenic Mice Exhibit Enhancedmentioning

confidence: 99%

“…Here, we describe that in vivo knockdown of Dock7 in mice that have a specific short-hairpin RNA (shRNA) yields a specific phenotype with enhanced myelin thickness in SCs without observable reduced axon thickness in PNS sciatic nerves. We previously cloned the dock7 gene and characterized Dock7 as a guanine-nucleotide exchange factor (GEF) that activates small GTPases of the Rho family, Rac1 and Cdc42 [7,8]. Rho GTPases are critical regulators that control cell morphological changes in many types of cells including SCs [9][10][11][12][13].…”

Section: Introductionmentioning

confidence: 99%

“…Rho GTPases are critical regulators that control cell morphological changes in many types of cells including SCs [9][10][11][12][13]. However, it remained unclear whether inhibition of Dock7 in vivo as well as in vitro affects myelination by SCs, or axon thickness in neurons, or both [8].…”

Section: Introductionmentioning

confidence: 99%

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Knockdown of Dock7 <i>in vivo</i> specifically affects myelination by Schwann cells and increases myelin thickness in sciatic nerves without affecting axon thickness

Torii¹,

Miyamoto²,

Nagao³

et al. 2012

AJMB

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During development of the peripheral nervous system (PNS), Schwann cells (SCs) wrap individual axons to form myelin sheaths, which act as surrounding insulators and markedly enhance the propagation of the action potential. In peripheral neuropathies such as Guillain-Barré syndrome (GBS) and inherited demyelinating Charcot-Marie-Tooth (CMT) disease and diabetic neuropathies, chronic demyelination and defective remyelination are repeated, causing more severe neuropathies. It is thus thought that development of a drug that promotes proper myelination with minimal side effects could provide an effective therapy for these diseases. As yet, however, little is known about therapeutic target molecules and genetically-modified mice for testing such approaches. We previously cloned the dock7 gene and characterized Dock7 as the regulator controlling SC myelination; however, an important issue, whether knockdown of Dock7 specifically affects myelination by SCs but not leaves neurons unaffected, has remained unclear. Here, we generate newly-produced transgenic mice harboring short-hairpin RNA (shRNA) targeting Dock7. We also describe that Dock7 shRNA transgenic mice exhibit enhanced myelin thickness without affecting axon thickness in sciatic nerves of the PNS, as reduced thickness of the axon diameter is the primary indicator of denatured neurons. Similarly, purified in vitro SC-neuronal cocultures established from transgenic mice exhibit an enhanced formation of myelin segments, suggesting that knockdown of Dock7 promotes myelination by SCs. Collectively, Dock7 knockdown specifically affects SC myelination in sciatic nerves, providing evidence that Dock7 may be a promising drug-target-specific molecules for developing a therapy for peripheral neuropathies that aims to enhance myelination.

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Section: Generation and Identification Of Shdock7 Transgenic Micementioning

confidence: 99%

Section: Cultures Of Primary Cells and In Vitro Myelinationmentioning

confidence: 99%

Section: Newly-generated Dock7 Shrna Transgenic Mice Exhibit Enhancedmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

See 3 more Smart Citations

Knockdown of Dock7 <i>in vivo</i> specifically affects myelination by Schwann cells and increases myelin thickness in sciatic nerves without affecting axon thickness

Torii¹,

Miyamoto²,

Nagao³

et al. 2012

AJMB

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Structural biology of DOCK‐family guanine nucleotide exchange factors

2022

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Edited by Jacqueline Cherfils DOCK proteins are a family of multi-domain guanine nucleotide exchange factors (GEFs) that activate the RHO GTPases CDC42 and RAC1, thereby regulating several RHO GTPase-dependent cellular processes. DOCK proteins are characterized by the catalytic DHR2 domain (DOCK DHR2 ), and a phosphatidylinositol(3,4,5)P 3 -binding DHR1 domain (DOCK DHR1 ) that targets DOCK proteins to plasma membranes. DOCK-family GEFs are divided into four subfamilies (A to D) differing in their specificities for CDC42 and RAC1, and the composition of accessory signalling domains. Additionally, the DOCK-A and DOCK-B subfamilies are constitutively associated with ELMO proteins that auto-inhibit DOCK GEF activity. We review structural studies that have provided mechanistic insights into DOCK-protein functions. These studies revealed how a conserved nucleotide sensor in DOCK DHR2 catalyses nucleotide exchange, the basis for how different DOCK proteins activate specifically CDC42 and RAC1, and sometimes both, and how upstream regulators relieve the ELMO-mediated auto-inhibition. We conclude by presenting a model for full-length DOCK9 of the DOCK-D subfamily. The involvement of DOCK GEFs in a range of diseases highlights the importance of gaining structural insights into these proteins to better understand and specifically target them.

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The regulation of DOCK family proteins on T and B cells

Chen

Chen²,

Yin

et al. 2020

Journal of Leukocyte Biology

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The dedicator of cytokinesis (DOCK) family proteins consist of 11 members, each of which contains 2 domains, DOCK homology region (DHR)-1 and DHR-2, and as guanine nucleotide exchange factors, they mediate activation of small GTPases. Both DOCK2 and DOCK8 deficiencies in humans can cause severe combined immunodeficiency, but they have different characteristics. DOCK8 defect mainly causes high IgE, allergic disease, refractory skin virus infection, and increased incidence of malignant tumor, whereas DOCK2 defect mainly causes early-onset, invasive infection with less atopy and increased IgE. However, the underlying molecular mechanisms causing the disease remain unclear. This paper discusses the role of DOCK family proteins in regulating B and T cells, including development, survival, migration, activation, immune tolerance, and immune functions. Moreover, related signal pathways or molecule mechanisms are also described in this review. A greater understanding of DOCK family proteins and their regulation of lymphocyte functions may facilitate the development of new therapeutics for immunodeficient patients and improve their prognosis.

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The Atypical Guanine-Nucleotide Exchange Factor, Dock7, Negatively Regulates Schwann Cell Differentiation and Myelination

Cited by 41 publications

References 63 publications

Knockdown of Dock7 <i>in vivo</i> specifically affects myelination by Schwann cells and increases myelin thickness in sciatic nerves without affecting axon thickness

Knockdown of Dock7 <i>in vivo</i> specifically affects myelination by Schwann cells and increases myelin thickness in sciatic nerves without affecting axon thickness

Structural biology of DOCK‐family guanine nucleotide exchange factors

The regulation of DOCK family proteins on T and B cells

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The Atypical Guanine-Nucleotide Exchange Factor, Dock7, Negatively Regulates Schwann Cell Differentiation and Myelination

Cited by 41 publications

References 63 publications

Knockdown of Dock7 &lt;i&gt;in vivo&lt;/i&gt; specifically affects myelination by Schwann cells and increases myelin thickness in sciatic nerves without affecting axon thickness

Knockdown of Dock7 &lt;i&gt;in vivo&lt;/i&gt; specifically affects myelination by Schwann cells and increases myelin thickness in sciatic nerves without affecting axon thickness

Structural biology of DOCK‐family guanine nucleotide exchange factors

The regulation of DOCK family proteins on T and B cells

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Product

Resources

About

Knockdown of Dock7 <i>in vivo</i> specifically affects myelination by Schwann cells and increases myelin thickness in sciatic nerves without affecting axon thickness

Knockdown of Dock7 <i>in vivo</i> specifically affects myelination by Schwann cells and increases myelin thickness in sciatic nerves without affecting axon thickness