brakeless is required for photoreceptor growth-cone targeting in Drosophila

Abstract

The R1-R6 subclass of photoreceptor neurons (R cells) in the Drosophila compound eye form specific connections with targets in the optic ganglia. In this paper, we report the identification of a gene, brakeless (bks), that is essential for R1-R6 growth cone targeting. In brakeless mutants, R1-R6 growth cones frequently fail to terminate migration in their normal target, the lamina, and instead project through it and terminate in the second optic ganglion, the medulla. Genetic mosaic analysis and transgene rescue experiments indicate that bks functions in R cells and not within the lamina target region. bks encodes a nuclear protein. We propose that it participates in a gene expression pathway regulating one or more growth cone components controlling R1-R6 targeting.N eurons form precise patterns of synaptic connections during development. Differentiating neurons extend axons that migrate along defined pathways toward their targets (1). The growth cone, a sensorimotor structure at the leading edge of the axon, plays a central role in axon guidance. It detects and integrates multiple signals (see, e.g., ref.2) and translates them into directed motility (see, e.g., ref.3). On reaching the target region, growth cone migration ceases and specific synapses are established. How growth cones select specific targets once they have reached the target region remains a central issue in developmental neurobiology.Considerable progress has been made in defining the molecular basis of targeting. In the chick visual system, for instance, the formation of a precise topographic map between retinal ganglion cells and tectal cells relies on the graded expression of the Ephrin ligands in the tectum and their receptors, the Ephs, on retinal ganglion cell growth cones (4). Antibody disruption experiments suggest that cadherins play an important role in subsequent steps in which retinal ganglion cells form specific connections in distinct laminae within the tectum (5). A large family of odorant receptors play an essential role in determining the precise patterns of connections made by olfactory neurons with their postsynaptic target cells (6). That targeting may rely on multiple signals, both attractive and repulsive in nature, is supported by the genetic analysis of motoneuron target specificity in the Drosophila embryo (2).Although targeting requires interactions between extracellular signals and receptors on the growth cone, the formation of neuronal connections also relies on the genetic programs that specify the precise spatial and temporal expression of these signaling molecules. Several transcription factors have been implicated in regulating axon guidance and target specificity (7-14). For instance, in Caenorhabditis elegans, a homeoboxcontaining protein UNC30 is required for normal pathfinding of a subset of axons suggesting that it may control the expression of specific guidance receptors; UNC-30 also controls genes necessary for other aspects of neuronal differentiation, including enzymes necessary for neurotransmitter metab...

Genetic Interactions Among scribbler, Atrophin and groucho in Drosophila Uncover Links in Transcriptional Repression

“…The scribbler (sbb) gene (aka brakeless and master-ofthickveins) encodes a novel nuclear protein of unknown function (Rao et al 2000;Senti et al 2000;Yang et al 2000;Funakoshi et al 2001). sbb mutations were uncovered through three different phenotypes: (1) abnormal turning behavior in larvae (Yang et al 2000); (2) an axon-targeting defect in the eye where some photoreceptors project to the wrong location in the optic lobe (Rao et al 2000;Senti et al 2000); and (3) deregulation of expression of the thickveins (tkv) gene in the wing imaginal disc (Funakoshi et al 2001).…”

Genetic and Molecular Characterization of Drosophia Brakeless: A Novel Modifier of Merlin Phenotypes

“…sbb is a dominant modifier of hypomorphic CycE phenotypes To test whether sbb modifies CycE phenotypes we recombined a marked P-element allele of CycE (CycE1°o°21 7 ) onto a null sbb allele (sbb 4 ;Rao et al, 2000) and a hypomorphic sbb allele (sbb 256 ). Sbb256 is a hypomorphic allele that expresses a strong enhancement of Merlin phenotypes (LaJeunesse et al, 2000).…”

“…Scribbler (sbb) is involved in a number of varied biological processes in Drosophila including foraging behavior (Yang et al, 2000), axon guidance, (Senti et al, 2000;Rao et al, 2000), dpp regulation via transcriptional regulation of thick veins (Funakoshi et al, 2001), and growth regulation (LaJeunesse et al, 2000). The sbb gene is highly expressed in the embryonic and larval nervous systems and in larval imaginal discs and encodes two novel nuclear proteins, a small 934 amino acid protein isoform called SbbA, and a larger 2023 amino acid isoform called SbbB (Yang et al, 2000, Senti et al, 2000.)…”

Alteration of wing size through over-expression ofscribblerisoforms

“…16 sbb has been implicated in varied biological processes including foraging, axon guidance, transcriptional regulation and dpp regulation. [17][18][19][20][21] The sbb gene encodes two novel nuclear proteins, a small protein isoform called SbbA, and…”