The establishment of axon trajectories is ultimately determined by the integration of intracellular signaling pathways. Here, a genetic approach in Drosophila has demonstrated that both Calmodulin and Son of sevenless signaling pathways are used to regulate which axons cross the midline. A loss in either signaling pathway leads to abnormal projection of axons across the midline and these increase with roundabout or slit mutations. When both Calmodulin and Son of sevenless are disrupted, the midline crossing of axons mimics that seen in roundabout mutants, although Roundabout remains expressed on crossing axons. Calmodulin and Son of sevenless also regulate axon crossing in a commissureless mutant. These data suggest that Calmodulin and Son of sevenless signaling pathways function to interpret midline repulsive cues that prevent axons crossing the midline (Fritz, 2000).
A novel CaM inhibitor, called kinesin-antagonist (KA), has been expressed using the neurogenic enhancer element of the fushi tarazu gene (ftzng) in a subset of CNS neurons that normally do not cross the midline. KA expression decreases endogenous CaM activation of target proteins in the growth cone and this leads to specific axon guidance defects including stalls at selected choice points, failure to fasciculate properly and abnormal crossing of the midline. robo and slit mutations and KA interact synergistically to increase the number of axon bundles abnormally crossing the midline. KA also induces axon bundles to cross the midline in the absence of Comm protein. Sos-dependent crossovers are enhanced by KA or by slit mutation. KA and Sos also interact to increase the number of axon bundles crossing in a comm mutant. Thus, the data demonstrate that both CaM and Sos signaling pathways are required to prevent certain axons crossing the midline (Fritz, 2000).
Whether CaM and Sos-mediated signaling is working directly downstream of Robo or in closely associated, but parallel signaling pathways to prevent axons from crossing is difficult to ascertain from this genetic data alone. If these signaling pathways lie downstream of Robo, the data suggest that both CaM and Sos are activated upon Slit binding to Robo, and result in growth cone repulsion. Interestingly, increased levels of calcium have been implicated in growth cone retraction and growth cone collapse, two ways in which a growth cone may respond to a repulsive agent. In addition, retrograde actin flow, which leads to filopodial retraction, is stimulated by CaM activation of myosin light chain kinase. Two other CaM target proteins, cAMP adenylyl cyclase and phosphodiesterase, regulate cAMP cellular concentrations thus altering neuronal response to Netrin 1 and other guidance cues. Activation of a Sos signaling pathway can affect cytoskeletal dynamics by activating various GTPases known to regulate growth cone behavior and axon guidance. Moreover, the cytoplasmic tail of Robo, known to be essential for signaling function, has a tyrosine residue that could recruit Sos via Drk or dreadlocks (dock), another SH2-SH3 adapter protein that affects axon guidance. Alternatively, Robo may bind Enabled, a known substrate for Abelson tyrosine kinase (Abl), which has been implicated in commissure formation. If Sos binds to phosphotyrosine residues on Ena (also via an adapter protein) it could be indirectly recruited to Robo (Fritz, 2000 and references therein).
Another possibility is that a disruption in both the CaM and Sos signaling pathways indirectly causes abnormal crossovers. CaM has been identified as a player downstream of several guidance molecules. Indeed, the gaps in the longitudinal connectives observed with increasing copies of KA in a comm mutant or in KA robo mutants, which are not seen in robo mutants alone, suggest CaM may function downstream of other guidance cue receptors to allow extension through the connective. Once these signals are attenuated by expression of KA, axons may inadvertently cross the midline. However, if CaM only functions in cell adhesive mechanisms within the connectives, it is difficult to explain why axons cross the midline in comm mutants when no other axons cross and the presence of Slit is still being read by Robo (Fritz, 2000 and references therein).
Since CaM and Sos appear to interpret a midline repulsive cue, the existence of an additional midline repulsion system working in parallel to Robo represents an interesting possibility. In robo mutants, axons cross the midline but then move to the longitudinal connective, instead of collapsing at the midline as observed in slit mutants. It has been suggested that this occurs because the continued presence of Slit at the midline is detected by a second receptor system, and candidate genes include a second robo gene or karussel. As the data shows, heterozygous slit mutations interact very strongly with single copies of KA, Sos or KA Sos together, to force axons across the midline. The interaction between Sos and slit mutations, especially when compared to the lack of Sos and robo interaction, is particularly striking. It seems that if the activity of both repulsion systems is decreased due to the reduction of a common ligand (Slit), a disruption in CaM and/or Sos signaling dramatically increases midline crossing errors. Most of these results, including the synergistic effects of KA and Sos, robo and slit mutations, the robo-like phenotype of KA Sos mutants, and the enhancement of crossovers in comm mutants can be explained by a parallel decrease in both midline repulsive systems upon disruption of the CaM and Sos signaling pathways. Thus while the mechanisms by which CaM and Sos contribute to an axon guidance decision at the midline remain unclear, the data clearly indicate that CaM and Sos signaling pathways are critical to the transduction of repulsive information at the midline (Fritz, 2000 and references therein).
Rho family GTPases are ideal candidates to regulate aspects of cytoskeletal dynamics downstream of axon guidance receptors. To examine the in vivo role of Rho GTPases in midline guidance, dominant negative (dn) and constitutively active (ct) forms of Rho, Drac1, and Dcdc42 are expressed in the Drosophila CNS. When expressed alone, only ctDrac and ctDcdc42 cause axons in the pCC/MP2 pathway to cross the midline inappropriately. Heterozygous loss of Roundabout enhances the ctDrac phenotype and causes errors in embryos expressing dnRho or ctRho. Homozygous loss of Son-of-Sevenless (Sos) also enhances the ctDrac phenotype and causes errors in embryos expressing either dnRho or dnDrac. CtRho suppresses the midline crossing errors caused by loss of Sos. CtDrac and ctDcdc42 phenotypes are suppressed by heterozygous loss of Profilin, but strongly enhanced by coexpression of constitutively active myosin light chain kinase (ctMLCK), which increases myosin II activity. Expression of ctMLCK also causes errors in embryos expressing either dnRho or ctRho. These data confirm that Rho family GTPases are required for regulation of actin polymerization and/or myosin activity and that this is critical for the response of growth cones to midline repulsive signals. Midline repulsion appears to require down-regulation of Drac1 and Dcdc42 and activation of Rho (Fritz, 2002).
Thus, when expressed alone, only ctDrac and ctDcdc42 cause midline crossing errors. However, the mutant GTPases interact genetically with mutations in robo, Sos, and chic and with overexpression of ctMLCK. The interactions are surprisingly specific. Midline crossing errors caused by expression of ctDrac or ctDcdc42 are suppressed by heterozygous loss of Profilin and enhanced by expression of ctMLCK. These results indicate that Drac1 and Dcdc42 encourage axons to cross the midline by regulating actin polymerization and/or myosin activity. CtRho and dnRho interact strongly with expression of ctMLCK or heterozygous loss of Robo, which suggests that regulation of myosin activity by Rho is crucial for midline repulsion. This work demonstrates that Rho, Drac1, and Dcdc42 are involved in dictating which axon may cross the midline, presumably by aiding in the transduction of attractive and/or repulsive cues operating at the midline. By using mutations in signaling molecules known to prevent pCC/MP2 axons from crossing the midline, this analysis concentrates on how Rho, Drac1, and Dcdc42 may regulate cytoskeletal dynamics in response to midline repulsive cues (Fritz, 2002).
Expression of dnRho may specifically interfere with retraction of filopodia in response to repulsive cues, leading to increased midline crossing errors. A global increase in myosin activity caused by expression of either ctRho or ctMLCK, or even a Rho GEF, may cause axon guidance errors by increasing the forward movement of the growth cone. Midline attractive activity (e.g., Netrins) probably also influences how much myosin activity is available to move a growth cone over the midline. The literature and these experiments are most consistent with a model in which Rho is activated by repulsive guidance signals. Activation of ephrinA5 receptors causes an increase in Rho activity resulting in a growth cone collapse. Plexin B, the receptor for repulsive semaphorins, binds to and seems to activate Rho. Activation of Robo by Slit recruits srGAP1, which appears to prevent it from binding to and inactivating Rho. The genetic interactions seen between Sose49 mutations and expression of ctRho or dnRho are consistent with Sos acting as a GEF for Rho in pCC/MP2 neurons. DnRho strongly enhances the midline crossing errors caused by loss of Sos, while ctRho almost completely suppresses them. Since Sos-dependent signaling pathways are required for response to midline repulsive cues, this is further evidence that Rho is activated downstream of repulsive guidance signals, although a role downstream of selected attractants cannot be ruled out (Fritz, 2002).
Clearly, regulation of Rho family GTPase activity is necessary to prevent axons from crossing the midline inappropriately. Midline repulsive signaling involves regulation of all three GTPases; Drac1 and Dcdc42 are likely downregulated, while Rho seems to be activated downstream of repulsive signals. The Rho family GTPases influence actin polymerization and/or myosin force generation to regulate the processes of growth cone motility that are required for proper response to axon guidance signals (Fritz, 2002).
The guanine nucleotide exchange factor (GEF) Son-of-sevenless (Sos) encodes a complex multidomain protein best known for its role in activating the small GTPase RAS in response to receptor tyrosine kinase (RTK) stimulation. Much less well understood is SOS's role in modulating RAC activity via a separate GEF domain. In the course of a genetic modifier screen designed to investigate the complexities of RTK/RAS signal transduction, a complementation group of 11 alleles was isolated and mapped to the Sos locus. Molecular characterization of these alleles indicates that they specifically affect individual domains of the protein. One of these alleles, SosM98, which contains a single amino acid substitution in the RacGEF motif, functions as a dominant negative in vivo to downregulate RTK signaling. These alleles provide new tools for future investigations of SOS-mediated activation of both RAS and RAC and how these dual roles are coordinated and coregulated during development (Silver, 2004).
Nervous system injury or disease leads to activation of glia, which govern postinjury responses in the nervous system. Axonal injury in Drosophila results in transcriptional upregulation of the glial engulfment receptor Draper; there is extension of glial membranes to the injury site (termed activation), and then axonal debris is internalized and degraded. Loss of the small GTPase Rac1 from glia completely suppresses glial responses to injury, but upstream activators remain poorly defined. Loss of the Rac guanine nucleotide exchange factor (GEF) Crk/myoblast city (Mbc)/dCed-12 has no effect on glial activation, but blocks internalization and degradation of debris. This study shows that the signaling molecules Downstream of receptor kinase (DRK) and Daughter of sevenless (DOS) (mammalian homologs, Grb2 and Gab2, respectively) and the GEF Son of sevenless (SOS) (mammalian homolog, mSOS) are required for efficient activation of glia after axotomy and internalization/degradation of axonal debris. At the earliest steps of glial activation, DRK/DOS/SOS function in a partially redundant manner with Crk/Mbc/dCed-12, with blockade of both complexes strongly suppressing all glial responses, similar to loss of Rac1. This work identifies DRK/DOS/SOS as the upstream Rac GEF complex required for glial responses to axonal injury, and demonstrates a critical requirement for multiple GEFs in efficient glial activation after injury and internalization/degradation of axonal debris (Lu, 2014).
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date revised: 23 August 2014
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