Maintaining neural function: the role of Gooseberry, the Pax 3/7 homologue in controlling synaptic growth, plasticity, and stability

Abstract

Although neurons are long-lived cells little is known about the mechanisms responsible for maintaining their properties and cellular stability. Here, we investigate the pair-rule transcription factor Gooseberry (Gsb), previously known to contribute to neuroblast and neuronal fate determination during early embryogenesis. Specifically, we ask whether Gsb is responsible for the maintenance of basic neuronal properties within developed and functioning motoneurons, after fate determination has occurred. Interestingly, we find it is required at late stages of neuronal life to curtail synaptic growth and plasticity. Gsb loss of function provokes overgrown and over-plastic synapses while its overexpression generates undergrown and under-plastic synapses. We also show that it is essential for the stability and integrity of the synapse. Indeed, genetic manipulations downregulating Gsb provoke synaptic retractions, a hallmark of neurodegenerative diseases. Using transgenic combinations allowing the temporal control of Gsb under- or overexpression, we show that these phenotypes can be generated long after Gsb's requirement for fate determination. In some cases, Gsb misexpression for tens of minutes or a few hours is sufficient to provoke drastic changes in fully mature motoneuron synapses. Finally, we show that Gsb's ability to regulate growth at the synapse is the result of its antagonism to the secreted Wingless signal (Wg, the Wnt homolog). We present the first evidence that Gsb acts downstream of Wg and upstream of the protein kinase Shaggy (the Gsk3β homolog) to antagonize the Wg signaling pathway. We also describe a possible neuroprotective role for Wg at the Drosophila NMJ. Lastly, we explore the role of a Wg pathway inhibitor, Casein Kinase 1α in vi synaptic growth, plasticity and stability and found that it resembles Gsb's effects at the synapse.