Collagen XIXa1 is crucial for motor axon navigation at intermediate targets

Abstract

SUMMARYDuring development, motor axons navigate from the spinal cord to their muscle targets in the periphery using stereotyped pathways. These pathways are broken down into shorter segments by intermediate targets where axon growth cones are believed to coordinate guidance cues. In zebrafish stumpy mutants, embryonic development proceeds normally; however, as trunk motor axons stall at their intermediate targets, suggesting that Stumpy is needed specifically for motor axon growth cones to proceed past intermediate targets. Fine mapping and positional cloning revealed that stumpy was the zebrafish homolog of the atypical FACIT collagen collagenXIXa1 (colXIX). colXIX expression was observed in a temporal and spatial pattern, consistent with a role in motor axon guidance at intermediate targets. Knocking down zebrafish ColXIX phenocopied the stumpy phenotype and this morpholino phenotype could be rescued by adding back either mouse or zebrafish colXIX RNA. The stumpy phenotype was also partially rescued in mutants by first knocking down zebrafish ColXIX and adding back colXIX RNA, suggesting that the mutation is acting as a dominant negative. Together, these results demonstrate a novel function for a FACIT collagen in guiding vertebrate motor axons through intermediate targets.

Slow Muscle Precursors Lay Down a Collagen XV Matrix Fingerprint to Guide Motor Axon Navigation

“…Lack of myotomal LH3 glycosyltransferase activity in the diwanka/lh3 mutant was suggested to be responsible for a motoneuron guidance defect through improper glycosylation of collagen XVIII (Schneider and Granato, 2006). Recently, analysis of the stumpy/col19a1 mutant revealed that collagen XIX also plays a crucial role in motor axon guidance at intermediate targets (Hilario et al, 2010). Collagen XV shares structural similarities with collagen XVIII as they both belong to the multiplexin (multiple triple helix interruptions) subset of the collagen superfamily (Ricard-Blum and Ruggiero, 2005).…”

“…Several ECM cues involved in zebrafish axon pathfinding (CS, tenascin C, collagens XVIII and XIX) have been identified mainly through the combined analysis of gene expression patterns and mutants deficient in primary motor axon pathfinding, such as diwanka/lh3 (Schneider and Granato, 2006), unplugged/ MuSK (Zhang et al, 2004), and stumpy/ col19a1 (Hilario et al, 2010). However, except in the case of tenascin-C , the presence of these molecular components in the motor path has not been shown.…”

ChondrolectinMediates Growth Cone Interactions of Motor Axons with an Intermediate Target

“…A number of factors have been found that specifically affect interactions of growing motor axons with the horizontal myoseptum choice point (Bernhardt and Schachner, 2000;RodinoKlapac and Beattie, 2004;Zhang et al, 2004;Schweitzer et al, 2005;Schneider and Granato, 2006;Hilario et al, 2010). Many of these factors are either extracellular matrix (ECM) components at the horizontal myoseptum or genes that modify the ECM.…”

Engrailed controls epaxial-hypaxial muscle innervation and the establishment of vertebrate three-dimensional mobility

“…Notably, our En1 gain-and loss-of-function mutations produced phenotypes distinct from that of FgfR1 loss-and gain-of-function mutants. In the zebrafish, local cues in the extracellular matrix have been proposed to facilitate the organised exit of motor neurons from the spinal cord (Hilario et al, 2010;Schneider and Granato, 2006); reviewed in (Lewis and Eisen, 2003). Yet, while all axons then use the common route to the site of eng expression, loss of eng expression produced much stronger phenotypes than the genetic or physical ablation of muscle pioneers (reviewed by Lewis and Eisen, 2003).…”

“…In the zebrafish, sema3aa, sema3ab, robo3 and a number of extracellular matrix molecules have been implicated in axonal repulsion, yet attraction to intermediate (choice points) and ultimate motor neurons targets is even more unclear than in amniotes (Halloran et al, 2000;Hilario et al, 2010;Sato-Maeda et al, 2006;Schneider and Granato, 2006); (reviewed by Lewis and Eisen, 2003). It has been proposed that differential responses of epaxial-hypaxial neurons to the same axon guidance molecule may be regulated intrinsically, elicited by the differential expression of receptors (SatoMaeda et al, 2006;Shirasaki et al, 2006).…”