The Notch ligand E3 ligase, Mind Bomb1, regulates glutamate receptor localization in Drosophila

Abstract

The postsynaptic density (PSD) is a protein-rich network important for the localization of postsynaptic glutamate receptors (GluRs) and for signaling downstream of these receptors. Although hundreds of PSD proteins have been identified, many are functionally uncharacterized. We conducted a reverse genetic screen for mutations that affected GluR localization using Drosophila genes that encode homologs of mammalian PSD proteins. 42.8% of the mutants analyzed exhibited a significant change in GluR localization at the third instar larval neuromuscular junction (NMJ), a model synapse that expresses homologs of AMPA receptors. We identified the E3 ubiquitin ligase, Mib1, which promotes Notch signaling, as a regulator of synaptic GluR localization. Mib1 positively regulates the localization of the GluR subunits GluRIIA, GluRIIB, and GluRIIC. Mutations in mib1 and ubiquitous expression of Mib1 that lacks its ubiquitin ligase activity result in the loss of synaptic GluRIIA-containing receptors. In contrast, overexpression of Mib1 in all tissues increases postsynaptic levels of GluRIIA. Cellular levels of Mib1 are also important for the structure of the presynaptic motor neuron. While deficient Mib1 signaling leads to overgrowth of the NMJ, ubiquitous overexpression of Mib1 results in a reduction in the number of presynaptic motor neuron boutons and branches. These synaptic changes may be secondary to attenuated glutamate release from the presynaptic motor neuron in mib1 mutants as mib1 mutants exhibit significant reductions in the vesicle-associated protein cysteine string protein and in the frequency of spontaneous neurotransmission.

The E3 Ubiquitin Ligase Mindbomb1 controls zebrafish Planar Cell Polarity

“…For this reason, numerous studies have turned to the functional inactivation of mib1 to inhibit Notch signaling in different biological contexts. A number of recent studies have however shown that the role of Mib1 extends beyond the Notch pathway (Li et al, 2011; Mizoguchi et al, 2017; Sturgeon et al, 2016; Villumsen et al, 2013; Čajánek et al, 2015). In the present study, we have identified a novel Notch-independent function of Mib1 in the regulation of PCP-dependent CE movements during zebrafish gastrulation.…”

“…In addition to Delta ligands, Mib1 is able to interact with a number of additional protein substrates (Berndt et al, 2011; Matsuda et al, 2016; Mertz et al, 2015; Tseng et al, 2014). Accordingly, functional studies have implicated Mib1 in a growing number of functions that include the regulation of epithelial morphogenesis (Dho et al, 2019; Matsuda et al, 2016) and cell migration (Mizoguchi et al, 2017), centrosome and cilia biogenesis (Douanne et al, 2019; Joachim et al, 2017; Villumsen et al, 2013; Wang et al, 2016; Čajánek et al, 2015), the control of glutamate receptor localization (Sturgeon et al, 2016) or interferon production (Li et al, 2011).…”

Post-Developmental Roles of Notch Signaling in the Nervous System

“…Furthermore, the authors found that Notch1 and GluN1 can physically interact based on co-immunoprecipitation experiments, which suggests that these proteins may also functionally interact. Links between Notch and glutamate signaling have also been suggested in the mouse cerebellum [ 136 , 137 ] and rat hippocampus [ 138 ] as well as in Drosophila [ 61 , 64 , 139 ] and C. elegans [ 140 ] nervous systems. However, the proposed mechanism of action is different in different studies.…”

microRNAs Sculpt Neuronal Communication in a Tight Balance That Is Lost in Neurological Disease

“…Mib1 is an E3 ubiquitin ligase that regulates late phase LTP as well as learning and memory (Yoon et al, 2012). In Drosophila , Mib1 also positively regulates the synaptic localization of GluRIIA, GluRIIB, and GluRIIC receptors, which are homologues of the mammalian AMPA receptor subunits (Sturgeon et al, 2016), thus providing an another potential link between miR-137 and glutamatergic signaling.…”