Axon sorting in the optic tract requires HSPG synthesis by ext2 (dackel) and extl3 (boxer).
Retinal ganglion cell (RGC) axons are topographically ordered in the optic tract according to their retinal origin. In zebrafish dackel (dak) and boxer (box) mutants, some dorsal RGC axons missort in the optic tract but innervate the tectum topographically. Molecular cloning reveals that dak and box encode ext2 and extl3, glycosyltransferases implicated in heparan sulfate (HS) biosynthesis. Both genes are required for HS synthesis, as shown by biochemical and immunohistochemical analysis, and are expressed maternally and then ubiquitously, likely playing permissive roles. Missorting in box can be rescued by overexpression of extl3. dak;box double mutants show synthetic pathfinding phenotypes that phenocopy robo2 mutants, suggesting that Robo2 function requires HS in vivo; however, tract sorting does not require Robo function, since it is normal in robo2 null mutants. This genetic evidence that heparan sulfate proteoglycan function is required for optic tract sorting provides clues to begin understanding the underlying molecular mechanisms.
Lee
Jeong-Soo
JS
Department of Neurobiology and Anatomy, University of Utah, 20 North 1900 East, Salt Lake City, Utah 84103, USA.
von der Hardt
Sophia
S
Rusch
Melissa A
MA
Stringer
Sally E
SE
Stickney
Heather L
HL
Talbot
William S
WS
Geisler
Robert
R
Nüsslein-Volhard
Christiane
C
Selleck
Scott B
SB
Chien
Chi-Bin
CB
Roehl
Henry
H
D000818:Animals; D001369:Axons / Q000378:metabolism*; D019812:Heparan Sulfate Proteoglycans / Q000096:biosynthesis* / Q000235:genetics; D008969:Molecular Sequence Data; D017351:N-Acetylglucosaminyltransferases / Q000096:biosynthesis / Q000235:genetics / Q000502:physiology*; D012165:Retinal Ganglion Cells / Q000378:metabolism; D014795:Visual Pathways / Q000196:embryology / Q000378:metabolism*; D015027:Zebrafish; D029961:Zebrafish Proteins / Q000502:physiology*; D000099065:Exostosin 2
C484685:Extl3 protein, mouse; D019812:Heparan Sulfate Proteoglycans; D029961:Zebrafish Proteins; C416220:dackel protein, zebrafish; D017351:N-Acetylglucosaminyltransferases; D000099065:Exostosin 2