The Forkhead transcription factor UNC-130 is required for the graded spatial expression of the UNC-129 TGF-β guidance factor in C. elegans

Abstract

Secreted proteins required for cellular movements along the circumference of the body wall inA fundamental question in development is how cellular movements are guided. Studying mutations that specifically affect guidance has proven to be an effective way to investigate this process. In the free-living nematode Caenorhabditis elegans, the secreted UNC-6/netrin guidance cue is expressed ventrally while UNC-5 and UNC-40/DCC (deleted in colorectal cancer), predicted receptors for UNC-6, are expressed in axons and cells that migrate along the dorsoventral (D/V) axis. UNC-5 and UNC-40 are required together for guidance away from UNC-6, while UNC-40 alone (or in combination with an undiscovered coreceptor) is required to guide migrations toward UNC-6 (Hedgecock et al. 1990;Ishii et al. 1992;Leung-Hagesteijn et al. 1992;Chan et al. 1996;Wadsworth et al. 1996). Studies with vertebrate homologs of these proteins suggest that guidance away from UNC-6/ netrin is mediated by direct interaction with UNC-5 and UNC-40/DCC, which induces growth-cone repulsion, whereas guidance toward UNC-6/netrin is mediated by direct interaction with UNC-40/DCC, which induces growth-cone attraction (Keino-Masu et al. 1996;Hong et al. 1999).In C. elegans, null mutations in unc-5 cause incompletely penetrant defects in dorsally oriented migrations, whereas null mutations in unc-40 or unc-6 cause incompletely penetrant defects in both dorsally and ventrally oriented migrations. Incomplete penetrance of single, double, and triple null mutants of these three genes suggest that they act in a single mechanism that guides migrations along the D/V axis and that other mechanisms act in parallel with UNC-6/netrin signaling to guide circumferential migrations (Hedgecock et al. 1990;Ishii et al. 1992;Leung-Hagesteijn et al. 1992;Chan et al. 1996). The incomplete effects of mutations in mouse netrin-1 and mouse DCC on circumferential axon guidance in the spinal cord similarly suggest that netrin-independent pathways also act to guide axons in the developing vertebrate spinal cord (Serafini et al. 1996;Fazeli et al. 1997). The nature of the parallel-acting D/V axon guidance mechanisms in C. elegans or in the mouse spinal cord has remained a mystery.

Reduced expression of BTBD10, an Akt activator, leads to motor neuron death

“…We crossed tm3335 and tm3607 with a C. elegans line, named evls82b, in which DB and DA neurons were labeled with the unc-129:: GFP reporter (Figure 3a). 21 In young-adult (4 days old) btbd-10(tm3335);evls82 and btbd-10(tm3607);evls82 worms, 10.9 % (n=129) Reduced expression of BTBD10 is neurotoxic M Nawa et al 14 DA and DB motor neurons were randomly lost and 6.7% and 7.8% of worms lost at least one DB and DA motor neurons, respectively, whereas no evls82 worms lost DB and DA neurons (Figure 3b). We also noted that 4.8% of btbd-10(tm3335);evls82 and 2.9% of btbd-10(tm3607);evls82 young-adult worms had at least one mislocalized DB or DA motor neurons, whereas no evls82 worms contained a mislocalized neuron (Figure 3c).…”

Genes That Control Ray Sensory Neuron Axon Development in the Caenorhabditis elegans Male

“…We found that unc-130(ev505) causes a mild ray axon defect similar to that seen in unc-6 and unc-40 mutants ( Figure 3D, Table 4). For dorsally orientated migrations of gonadal distal tip cells and for dorsoventral guidance of growth cones in formation of the motor neuron commissures, unc-130 acts in a pathway parallel to the UNC-6/netrin guidance pathway (Nash et al 2000). It encodes a forkhead transcription factor that acts by repressing unc-129 expression in ventral body muscles (Nash et al 2000).…”

“…For dorsally orientated migrations of gonadal distal tip cells and for dorsoventral guidance of growth cones in formation of the motor neuron commissures, unc-130 acts in a pathway parallel to the UNC-6/netrin guidance pathway (Nash et al 2000). It encodes a forkhead transcription factor that acts by repressing unc-129 expression in ventral body muscles (Nash et al 2000). We examined the effect of mutation in unc-129, which encodes a C. elegans TGF-b involved in motor axon guidance .…”

“…unc-130 had been shown to act in a pathway parallel to UNC-6/UNC-40 by repressing expression of the TGF-b family growth factor gene unc-129. Its role in guidance of the ray neurons may be through a different mechanism, because mutation in unc-129 had no effect on the ray axons, although it is required for normal formation of the rays Nash et al 2000;Ikegami et al 2004). However, UNC-129 might be redundant with another gene in ray axon guidance, the unc-130 phenotype being due to ectopic unc-129 expression.…”

Fishing lines, time‐delayed guideposts, and other tricks used by developing pharyngeal neurons in Caenorhabditis elegans

“…A mutation in unc-119, which encodes a protein acting as a regulator of axon branching (Maduro and Pilgrim, 1995;Knobel et al, 2001), caused axon length defects in both the NSM (shorter axons) and M2 (longer axons) neurons, but caused excessive branching only in the M2 neurons. A mutation in the unc-129/TGFbeta pathway, which guides circumferential axons in C. elegans Nash et al, 2000;Ikegami et al, 2004), causes truncations or loss of the NSM major processes, but has little effect on the M2 neurons. Similarly, a mutation in the semaphorin-2 gene, smp-2 Ikegami et al, 2004), cause absence or truncation of the NSM major processes, but has no effects on the M2 neurons or the NSM thin process.…”