Rho-associated protein kinases (ROCKs) play key roles in mediating the control of the actin cytoskeleton by Rho family GTPases in response to extracellular signals. Such signaling pathways contribute to diverse neuronal functions from cell migration to axonal guidance to dendritic spine morphology to axonal regeneration to cell survival. In this review, the authors summarize biochemical knowledge of ROCK function and categorize neuronal ROCK-dependent signaling pathways. Further study of ROCK signal transduction mechanisms and specificities will enhance our understanding of brain development, plasticity, and repair. The ROCK pathway also provides a potential site for therapeutic intervention to promote neuronal regeneration and to limit degeneration. KeywordsRho GTPase; Cytoskeleton; Rho-associated kinase; Signal transduction; Axonal outgrowthThe cytoplasmic Rho family of GTPases plays a critical role in regulating actin microfilament dynamics. The control of cell shape and cell migration by Rho GTPases has attracted intense interest from the fields of cancer biology and cardiovascular medicine. More recently, it has become clear that Rho family proteins and their intracellular effectors participate in a range of neuronal functions from axonal growth to neuronal differentiation to neuronal survival to regeneration.The Rho-associated kinases (ROCKs) are principal mediators of RhoA activity, especially in the nervous system, and are the focus of this review. We explore current knowledge regarding the downstream targets and functions of ROCKs. In addition, we summarize known transduction mechanisms from extracellular neuronal signals to ROCK. By analyzing the upstream receptors, effectors, and mediators of Rho GTPase-related neuronal morphogenesis, we group these pathways functionally and biochemically. Rho-GTPasesBy sequence homology, the Ras-superfamily of GTPases can be subdivided into 9 families: Ras, Rab, Arf, Ran, Rad, Rheb, Rag, Rit and Rho (Blumenstein 2004 RhoA (Structure and Posttranslational Modification)Here, we focus on RhoA, a small GTPase of about 24 kDa (Kamai and others 2004) that has been extensively studied. This protein's CAAX-box is composed of the amino acids cysteine (C), leucine (L), valine (V), and leucine (L). Mutation of the X-amino acid of a ras peptide to leucine (Seabra and others 1991), as well as the examination of a variety of small guanine nucleotide binding proteins in which X = leucine or phenylalanine (Kawata and others 1990; Maltese and others 1990; Buss and others 1991; Yamane and others 1991; Leung and others 2007), revealed that these amino acids specify prenylation with geranylgeranyl by protein geranylgeranyltransferase type 1. In Rho family proteins where X = serine, methionine, glutamine, or alanine, prenylation is catalyzed by protein farnesyl transferase to add a farnesyl group. As predicted by its sequence, RhoA is modified by a thioether linkage of C20 geranylgeranyl to the COOH-terminal cysteine residue ( Figure 2.Although the two ROCK isoforms share 65%...

Rho GTPases are thought to mediate the action of several axonal growth inhibitors in the adult brain and spinal cord. RhoA has been targeted pharmacologically in both humans and animals to promote neurite outgrowth and functional recovery following CNS trauma. However, rat spinal cord injury studies suggest a complicated and partial benefit of inhibiting Rho or its downstream effector, Rho-associated kinase (ROCKII). This limited benefit may reflect inhibition of other kinases, poor access, or a minimal role of ROCKII in vivo. Therefore, we studied ROCKII mutant mice to probe this pathway genetically. ROCKII−/− dorsal root ganglion neurons are less sensitive to inhibition by Nogo protein or by chondroitin sulfate proteoglycan in vitro. We examined adult ROCKII−/− mice in two injury paradigms, cervical multilevel dorsal rhizotomy and midthoracic dorsal spinal cord hemisection. After dorsal root crush injury, the ROCKII−/− mice recovered use of the affected forepaw more quickly than did controls. Moreover, multiple classes of sensory axons regenerated across the dorsal root entry zone into the spinal cord of mice lacking ROCKII. After the spinal cord injury, ROCKII−/− mice showed enhanced local growth of raphespinal axons in the caudal spinal cord and corticospinal axons into the lesion site. Improved functional recovery was not observed by Basso Mouse Scale score following dorsal hemisection, likely due to developmental defects in the nervous system. Together, these findings demonstrate that the ROCKII gene product limits axonal growth after CNS trauma.

Initially discovered as a potent neurite outgrowth inhibitor in the central nervous system (CNS), Nogo-A has emerged as a multifunctional protein. Involvement of this protein has been demonstrated in numerous developmental processes, ranging from cell migration, axon guidance and fasciculation, dendritic branching and CNS plasticity to oligodendrocyte differentiation and myelination. Although initially necessary and beneficial for shaping and later maintaining CNS structure and functionality, the growth restricting properties of Nogo-A can have negative effects on nervous system injury or disease. Hence, correlating with its various neurobiological roles, Nogo-A was implicated in a range of CNS disturbances, including trauma such as spinal cord injury or stroke, neurodegenerative diseases such as Alzheimer's disease, amyotrophic lateral sclerosis or multiple sclerosis, or in schizophrenia. In this review, we summarize the current state of knowledge for Nogo-A's involvement in these nervous system diseases and perturbations and discuss the possible underlying mechanisms. Furthermore, we provide a comprehensive overview on molecular signaling pathways as well as structural properties identified for Nogo-A and point to open questions in the field.

Central nervous system injury results in the release of molecules that inhibit neuronal regeneration, but retinoic acid counteracts this effect by inhibiting Lingo-1.