Axon Guidance

Dscam’s Double Duty

Science Signaling  18 Nov 2008:
Vol. 1, Issue 46, pp. ec392
DOI: 10.1126/scisignal.146ec392

Down Syndrome cell adhesion molecule (Dscam) is a member of a family of immunoglobulin proteins that homooligomerize. Andrews et al. report that Dscam also functions as a receptor for netrins, neural guidance cues that bind to the receptor Frazzled (Fra) in Drosophila melanogaster and deleted in colorectal cancer (DCC) in vertebrates. Drosophila embryos carrying loss-of-function mutations in Dscam (one of four Dscam genes in the fly), fra, or both netrin genes (NetA and NetB) exhibited similar phenotypes that were comparable in severity but varied in penetrance. Animals of each genotype exhibited pathfinding and fasciculation defects in Bolwig’s Nerve, a bundle of axons that connects Bolwig’s organ, the larval photosensor, to the brain. These defects were present in up to 96% of NetA,B homozygotes, in about 60% of Dscam;fra double homozygotes, and in about 26% of animals homozygous for either Dscam or fra mutations, suggesting that Dscam could function as a netrin receptor in parallel to Fra. Mutant phenotypes were also observed in transheterozygotes carrying various combinations of Dscam, fra, and NetA,B loss-of-function alleles, suggesting that these three genes function in the same pathway. Additional genetics experiments indicated that Dscam also mediated netrin signaling during migration of salivary glands and axonal midline crossing and that Dscam mediated signaling from other chemoattractants in addition to netrins. Dscam and netrin physically interacted in a cell overlay assay in which COS-7 cells expressing fly or human Dscam (dDscam or hDscam, respectively) were incubated with Myc-tagged NetB from fly or Myc-tagged Netrin-1 from chick (cNet-1) and then immunostained with an antibody that recognizes the Myc epitope. Both chick and fly netrins bound to COS-7 cells expressing dDscam or hDscam; therefore, the netrin-binding ability of Dscam is conserved across species. The dissociation constant (Kd) for cNet-1 bound to hDscam was similar to the Kd for cNet-1 bound to rat DCC. Immunohistochemical staining showed that Dscam was present in axons of netrin-responsive commissural axons in the mouse, consistent with Dscam functioning as a netrin receptor in vivo in vertebrates. This newly identified role for Dscam as a receptor for netrins (and possibly additional ligands) in mediating migration of both neurons and salivary glands may shed new light on the pleiotropic neurogenesis and organogenesis phenotypes associated with Down Syndrome.

G. L. Andrews, S. Tanglao, W. T. Farmer, S. Morin, S. Brotman, M. A. Berberoglu, H. Price, G. C. Fernandez, G. S. Mastick, F. Charron, T. Kidd, Dscam guides embryonic axons by Netrin-dependent and -independent functions. Development 135, 3839–3848 (2008). [Abstract] [Full Text]