Rho GTPases are key regulators of cytoskeletal dynamics and affect many cellular processes, including cell polarity, migration, vesicle trafficking and cytokinesis. These proteins are conserved from plants and yeast to mammals, and function by interacting with and stimulating various downstream targets, including actin nucleators, protein kinases and phospholipases. The roles of Rho GTPases have been extensively studied in different mammalian cell types using mainly dominant negative and constitutively active mutants. The recent availability of knockout mice for several members of the Rho family reveals new information about their roles in signalling to the cytoskeleton and in development.
There are 20 members of the Rho GTPase family in mammals; all eukaryotes have several Rho GTPases.
Rho GTPases regulate cytoskeletal dynamics, cell polarity, cell migration, cell-cycle progression, vesicle trafficking and cytokinesis.
Most studies into the function of Rho GTPases in mammalian systems have used cultured cells that express constitutively active and/or dominant-negative mutants.
Knockout mice for five Rho GTPases — RhoB, RhoC, RAC2, RAC3 and RhoH — are viable and fertile, allowing studies of their functions in vivo and in cells purified from tissues. So far, these studies have mostly shown that each of these GTPases has a similar role in vivo to that predicted from in vitro studies.
Knockout mice for Rac1 and Cdc42 die early in embryogenesis, and hence conditional knockout alleles have been generated to study their function.
The effects of knocking out Rac1 or Cdc42 have been investigated in multiple tissues and cell types in mice, from haematopoietic cells to neurons, glial cells, and epithelial cells; these studies have revealed novel functions for RAC1 and CDC42 that had not been predicted from in vitro analysis of cell lines.
In some cases, knockout of Rac1 or Cdc42 gives a different phenotype to expression of dominant negative RAC1 or dominant-negative CDC42; for example, dominant-negative CDC42 inhibits filopodium extension, but CDC42-null fibroblastoid cells can still make filopodia. However, CDC42-null neurons have a reduced number of filopodia. These results suggest that CDC42 contribution to filopodium extension is cell-type-specific.
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We apologize to all those authors in the field whose papers we could not cite because of space limitations. We thank members of our laboratory for discussions. Work in our laboratory is supported by the Medical Research Council UK, Cancer Research UK and the European Commission Network of Excellence, MAIN.
A family of proteins that bind to the barbed end of actin filaments and regulate actin dynamics.
- Actin-filament severing
The disruption of interactions between neighbouring actin molecules in actin filaments such that the filament is cut in two. Actin-filament severing proteins include gelsolin and villin.
- Glial cells
Non-neuronal cells of the nervous system that provide support and nutrition for neurons. They also form myelin and contribute to axon guidance.
Multiple layers of plasma membrane made by glial cells that wrap around axons and electrically insulate them. Myelin contains high levels of glycolipids and myelin-specific proteins.
- Embryoid bodies
Aggregates of embryonic stem cells that are used to model the early steps of peri-implantation embryonic development, including establishment of epithelial polarity.
- Barbed ends
The fast-growing ends of actin filaments, so-called because of their appearance in electron micrographs following binding of a fragment of myosin.
- Capping proteins
Proteins that bind to the ends of actin filaments and prevent actin polymerization.
A family of large, mostly α-helical proteins that form a plasma-membrane-associated lattice that consists of spectrin tetramers and short actin filaments.
- Phagocytic cup
Plasma membrane extension around a particle that is in the process of being engulfed by phagocytosis.
- Farnesyl transferase
An enzyme that adds a 15-carbon isoprenoid called a farnesyl group to a Cys residue near the C terminus of a number of proteins, including several Rho GTPases. Other Rho GTPases, such as RhoA and RAC1, are modified by the addition of a 20-carbon geranylgeranyl group.
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