Receptor tyrosine phosphatases regulate axon guidance across the midline of the Drosophila embryo

Abstract

Neural receptor-linked protein tyrosine phosphatases (RPTPs) are required for guidance of motoneuron and photoreceptor growth cones in Drosophila. These phosphatases have not been implicated in growth cone responses to specific guidance cues, however, so it is unknown which aspects of axonal pathfinding are controlled by their activities. Three RPTPs, known as DLAR, DPTP69D, and DPTP99A, have been genetically characterized thus far. Here we report the isolation of mutations in the fourth neural RPTP, DPTP10D. The analysis of double mutant phenotypes shows that DPTP10D and DPTP69D are necessary for repulsion of growth cones from the midline of the embryonic central nervous system. Repulsion is thought to be triggered by binding of the secreted protein Slit, which is expressed by midline glia, to Roundabout (Robo) receptors on growth cones. Robo repulsion is downregulated by the Commissureless (Comm) protein, allowing axons to cross the midline. Here we show that the Rptp mutations genetically interact with robo, slit and comm. The nature of these interactions suggests that DPTP10D and DPTP69D are positive regulators of Slit/Roundabout repulsive signaling. We also show that elimination of all four neural RPTPs converts most noncrossing longitudinal pathways into commissures that cross the midline, indicating that tyrosine phosphorylation controls the manner in which growth cones respond to midline signals.

Roles of glycosaminoglycans as regulators of ligand/receptor complexes

“…Receptor protein tyrosine phosphatases (RPTPs) act in the repulsion of axonal growth cones from the midline in embryonic development by interacting with the Slit (guidance cue)/ Robo (receptor) signalling system [23], for instance, by binding of Drosophila Robo3 and RPTP69d [24]. Moreover, RPTPs acts in the formation of excitatory synapses [25,26].…”

Sticks and Stones, a conserved cell surface ligand for the Type IIa RPTP Lar, regulates neural circuit wiring in Drosophila

“…Analysis of Type IIa RPTP function is complicated by redundancy among the three proteins, which are very similar to each other and are expressed in overlapping patterns. Redundancy among RPTPs has been well characterized in Drosophila , where Lar Ptp69D , Ptp10D Ptp69D , and Ptp10D Ptp4E double mutants have unique phenotypes that are not present in single mutants ( Desai et al, 1997 ; Hakeda-Suzuki et al, 2017 ; Jeon et al, 2008 ; Jeon and Zinn, 2009 ; Sun et al, 2000 ).…”

Complex protein interactions mediate Drosophila Lar function in muscle tissue

“…Due to the redundancy of RPTP function in mammals, key insights into neural regulation were confirmed in Drosophila, whereby Dlar [21], Ptp69D [22] or Ptp52F [23] single mutants display motor axon pathfinding defects during innervation of body wall muscle targets. In contrast, mutants of Ptp99A and Ptp10D require concomitant mutations in Dlar, Ptp69D, or Ptp52F to produce neural phenotypes [22][23][24][25][26]. Double, triple or quadruple mutants reveal intricate interactions that can be synergistic or antagonistic [27].…”