BMP Receptor Activates LIMK to Stabilize Synapses

Science's STKE  06 Sep 2005:
Vol. 2005, Issue 300, pp. tw321
DOI: 10.1126/stke.3002005tw321

The neuromuscular junction (NMJ) in Drosophila was used as a model system to uncover novel signaling processes that control synaptic stability. Mutations that disrupt bone morphogenic protein (BMP) signaling inhibit synaptic growth, leading to a reduced number of boutons and an increase in the number of "synaptic footprints," sites where the nerve has retracted from a synapse. Eaton and Davis report that these two functions of the BMP system can be separated and that synaptic stability relies on signaling through the type II BMP receptor [Wishful Thinking (Wit) to LIM kinase 1 (DLIMK1 in Drosophila)], whereas synaptic growth requires the canonical BMP pathway acting through Smads. The authors used genetic analysis to show that the canonical BMP components--Wit, Tkv (thick veins, a type I BMP receptor), Mad, and Medea (Smads)--increase synaptic footprints and decrease synaptic boutons at the fly NMJ. Expression of a truncated form of the receptor Wit that lacked a portion of the C-terminal region that is dispensable for Smad signaling restored synaptic bouton number, but these NMJ continued to exhibit elevated numbers of footprints, suggesting that the synaptic stability defect was not rescued. This C-terminal region interacted with the LIM and LIM-PDZ domains of DLIMK1 in yeast two-hybrid experiments, and the two proteins colocalized when expressed in S2 cells. In the motoneurons, DLIMK1 was localized to a cytosolic filamentous compartment that was near, but not identical to or dependent on, microtubules. Deficiency of DLIMK caused an increase in synaptic footprints without affecting the number of synaptic boutons. Expression of a dominant-negative DLIMK1 in neurons promoted synapse retraction, whereas expression in muscle did not. Overexpression of wild-type DLIMK1 in the wit background completely rescued not only synaptic stability but also synaptic growth and animal viability, with large numbers of mobile adult flies emerging; the wit flies typically die in a midlarval stage. This viability and synaptic growth and function rescue are perplexing but may be the result of hyperstabilization of synapses in the presence of excess DLIMK1, which then allows a second growth factor pathway to assume the role of synaptic growth stimulation. These results provide evidence for a Smad-independent signaling pathway from BMP receptors and provide in vivo support and physiological relevance for the in vitro data from mammals, suggesting that BMP receptors stimulate LIMK1.

B. A. Eaton, G. W. Davis, LIM kinase1 controls synaptic stability downstream of the type II BMP receptor. Neuron 47, 695-708 (2005). [PubMed]