The Making of a Synapse Target-Derived Signals and Presynaptic Differentiation

cells occupy the innermost layer of the cerebral cortex and are synapsed upon by mossy fibers that originate from the pontine nuclei as well as other somatosensory centers. Several features of in vivo synapse formation at the mossy fiber–granule cell synapse are recapitu-lated in this culture system, including a characteristic enlargement of the mossy fiber growth cone that pre-Presynaptic differentiation is a remarkable cellular event. cedes synapse formation. At the correct time and place, a motile growth cone is Granule cells normally express the secreted signaling transformed into a stable synaptic contact. In the case of molecule WNT7a during the period of synapse formation en passent synapse formation, a similar transformation in the cerebellum from P12 to P22. In their recent study, occurs at specific locations along an axon length. In Hall et al. (2000) report several experiments demonstrat-both instances, this transformation requires spatially ing that WNT7a is involved in axonal remodeling events and temporally controlled changes in cell shape that that may represent the initial events of synapse forma-are driven by cytoskeletal rearrangement. During this tion including growth cone spreading and cytoskeletal process, synaptic proteins are recruited to the forming rearrangement. WNT7a, when presented to mossy fiber synapse and are rapidly assembled into an intercellu-axons in either a cell surface or soluble form, causes lar junction that is capable of high-fidelity neurotrans-axon spreading and an increase in the size and complex-mission. ity of the growth cone. These effects of WNT7a mimic While we are gaining remarkable insight into the the effects of ganglion cell conditioned media, sug-mechanisms of postsynaptic differentiation, the mole-gesting that WNT7a is a factor secreted by ganglion cules that stimulate presynaptic differentiation remain cells that induces this process in vivo. Furthermore, the obscure. Even at the vertebrate neuromuscular junction effects of granule cell conditioned media can be blocked (NMJ), arguably the most well-characterized synapse in by the addition of a WNT signaling antagonist, sFRP-1. the nervous system, the factors that drive presynaptic differentiation are unknown (reviewed by Sanes and A canonical signaling pathway has been established Lichtman, 1999). Agrin and neuregulin are released from downstream of WNT/Wingless signaling. WNT signals the presynaptic motoneuron and act through MuSK and are transduced via frizzled receptors (fz) to activate an erbB kinases, respectively, to induce the clustering and intracellular signaling cascade that represses the activ-synthesis of postsynaptic acetylcholine receptors (re-ity of glycogen synthase 3␤ kinase (GSK3␤). GSK3␤ is viewed …