Involvement of Rho-family GTPases in axon branching
Development of the nervous system requires efficient extension and guidance of axons and dendrites culminating in synapse formation. Axonal growth and navigation during embryogenesis are controlled by extracellular cues. Many of the same extracellular signals also regulate axonal branching. The emergence of collateral branches from the axon augments the complexity of nervous system innervation and provides an additional mechanism for target selection. Rho-family GTPases play an important role in regulating intracellular cytoskeletal and signaling pathways that facilitate axonal morphological changes. RhoA/G and Rac1 GTPase functions are complex and they can induce or inhibit branch formation, depending on neuronal type, cell context or signaling mechanisms. Evidence of a role of Cdc42 in axon branching is mostly lacking. In contrast, Rac3 has thus far been implicated in the regulation of axon branching. Future analysis of the upstream regulators and downstream effectors mediating the effects of Rho-family GTPase will provide insights into the cellular processes effected, and shed light on the sometimes opposing roles of these GTPases in the regulation of axon branching.
PleiotRHOpic: Rho pathways are essential for all stages of Neural Crest development
Neural Crest (NC) cells are a multipotent migratory stem cell population unique to vertebrates, which contributes extensively to the formation of a wide array of neural and non-neural structures in the embryo. NC cells originate in the ectoderm at the border of the neural tube, undergo an epithelial-mesenchymal transition and acquire outstanding individual and collective migratory properties that allow them to disseminate and differentiate to different parts of the body. This exquisite capacity to switch from an epithelium to motile cells represents both a puzzling biological issue and an attractive model to address the basic mechanisms of cell migration and their alteration during cancer progression. Here we review how signaling pathways controlled by Rho GTPases, key players in cell adhesion, contraction, migration and polarity, contribute to the control the different phases of NCC development.
Modulation of osteoclast differentiation and bone resorption by Rho GTPases
Bone is a dynamic tissue constantly renewed through a regulated balance between bone formation and resorption. Excessive bone degradation by osteoclasts leads to pathological decreased bone density characteristic of osteolytic diseases such as post-menopausal osteoporosis or bone metastasis. Osteoclasts are multinucleated cells derived from hematopoietic stem cells via a complex differentiation process. Their unique ability to resorb bone is dependent on the formation of the actin-rich sealing zone. Within this adhesion structure, the plasma membrane differentiates into the ruffled border where protons and proteases are secreted to demineralize and degrade bone, respectively. On the bone surface, mature osteoclasts alternate between stationary resorptive and migratory phases. These are associated with profound actin cytoskeleton reorganization, until osteoclasts die of apoptosis. In this review, we highlight the role of Rho GTPases in all the steps of osteoclasts differentiation, function and death and conclude on their interest as targets for treatment of osteolytic pathologies.
Insulin is secreted into blood vessels from β cells of pancreatic islets in response to high blood glucose levels. Insulin stimulates an array of physiological responses in target tissues, including liver, skeletal muscle, and adipose tissue, thereby reducing the blood glucose level. Insulin-dependent glucose uptake in skeletal muscle and adipose tissue is primarily mediated by the redistribution of the glucose transporter type 4 from intracellular storage sites to the plasma membrane. Evidence for the participation of the Rho family GTPase Rac1 in glucose uptake signaling in skeletal muscle has emerged from studies using cell cultures and genetically engineered mice. Herein, recent progress in understanding the function and regulation of Rac1, especially the cross-talk with the protein kinase Akt2, is highlighted. In addition, the role for another Rho family member TC10 and its regulatory mechanism in adipocyte insulin signaling are described.
The on-off relationship of Rho and Rac during integrin-mediated adhesion and cell migration
Rho GTPases play an essential role in regulating cell spreading, adhesion, and migration downstream of integrin engagement with the extracellular matrix. In this review, we focus on RhoA and Rac1—2 Rho GTPases which are required for efficient adhesion and migration—and describe how specific guanine nucleotide exchange factors (GEFs) and GTPase-activating proteins (GAPs) regulate the extensive crosstalk that exists between them. In particular, we assess the role of GEFs and GAPs in light of recent, unexpected evidence concerning the spatiotemporal relationship between RhoA and Rac1 at the leading edge of migrating cells. Force is increasingly recognized as a key regulator of cell adhesion and we highlight the role of GEFs and GAPs in mechanotransduction, before debating the controversial role of tension in focal adhesion maturation.
Rho, nuclear actin, and actin-binding proteins in the regulation of transcription and gene expression
Actin cytoskeleton is one of the main targets of Rho GTPases, which act as molecular switches on many signaling pathways. During the past decade, actin has emerged as an important regulator of gene expression. Nuclear actin plays a key role in transcription, chromatin remodelling and pre-mRNA processing. In addition, the “status” of the actin cytoskeleton is used as a signaling intermediate by at least the MKL1-SRF and Hippo-pathways, which culminate in the transcriptional regulation of cytoskeletal and growth-promoting genes, respectively. Rho GTPases may therefore regulate gene expression by controlling either cytoplasmic or nuclear actin dynamics. Although the regulation of nuclear actin polymerization is still poorly understood, many actin-binding proteins, which are downstream effectors of Rho, are found in the nuclear compartment. In this review, we discuss the possible mechanisms and key proteins that may mediate the transcriptional regulation by Rho GTPases through actin.