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Terminal selectors are transcription factors that control neuronal identity by regulating expression of key effector molecules, such as neurotransmitter biosynthesis proteins and ion channels. Whether and how terminal selectors control neuronal connectivity is poorly understood. Here, we report that UNC-30 (PITX2/3), the terminal selector of GABA nerve cordmotor neurons in Caenorhabditis elegans, is required for neurotransmitter receptor clustering, a hallmark of postsynaptic differentiation. Animals lacking unc-30 or madd-4B, the short isoform of the motor neuron-secreted synapse organizer madd-4 (punctin/ADAMTSL), display severe GABA receptor type A (GABAAR) clustering defects in postsynaptic muscle cells. Mechanistically, UNC- 30 acts directly to induce and maintain transcription of madd-4B and GABA biosynthesis genes (e.g. unc-25/GAD, unc-47/VGAT). Hence, UNC-30 controls GABAA receptor clustering in postsynaptic muscle cells and GABA biosynthesis in presynaptic cells, transcriptionally coordinating two crucial processes for GABA neurotransmission. Further, we uncover multiple target genes and a dual role for UNC-30 as both an activator and a repressor of gene transcription. Our findings on UNC-30 function may contribute to our molecular understanding of human conditions, such as Axenfeld--Rieger syndrome, caused by PITX2 and PITX3 gene variants. [ABSTRACT FROM AUTHOR]

Author(s): Berangere Pinan-Lucarre [1, 2, 4]; Haijun Tu [1, 2, 4]; Marie Pierron [1, 2]; Pablo Ibanez Cruceyra [1]; Hong Zhan [1, 2]; Christian Stigloher [1, 5]; Janet E. Richmond [...]

The localization and clustering of neurotransmitter receptors at appropriate postsynaptic sites is a key step in the control of synaptic transmission. Here, we identify a novel paradigm for the synaptic localization of an ionotropic acetylcholine receptor (AChR) based on the direct interaction of its extracellular domain with a cell adhesion molecule of the IgLON family. Our results show that RIG-5 and ZIG-8, which encode the sole IgLONs in C. elegans, are tethered in the pre- and postsynaptic membranes, respectively, and interact in vivo through their first immunoglobulin-like (Ig) domains. In addition, ZIG-8 traps ACR-16 via a direct cis- interaction between the ZIG-8 Ig2 domain and the base of the large extracellular AChR domain. Such mechanism has never been reported, but all these molecules are conserved during evolution. Similar interactions may directly couple Ig superfamily adhesion molecules and members of the large family of Cys-loop ionotropic receptors, including AChRs, in the mammalian nervous system, and may be relevant in the context of IgLON-associated brain diseases.

Terminal selectors are transcription factors that control neuronal identity by regulating the expression of key effector molecules, such as neurotransmitter (NT) biosynthesis proteins, ion channels and neuropeptides. Whether and how terminal selectors control neuronal connectivity is poorly understood. Here, we report that UNC-30 (PITX2/3), the terminal selector of GABA motor neuron identity in C. elegans , is required for NT receptor clustering, a hallmark of postsynaptic differentiation. Animals lacking unc-30 or madd-4B, the short isoform of the MN-secreted synapse organizer madd-4 ( Punctin/ADAMTSL ), display severe GABA receptor type A (GABA A R) clustering defects in postsynaptic muscle cells. Mechanistically, UNC-30 acts directly to induce and maintain transcription of madd-4B and GABA biosynthesis genes (e.g., unc-25/GAD , unc-47/VGAT ). Hence, UNC-30 controls GABA A R clustering on postsynaptic muscle cells and GABA biosynthesis in presynaptic cells, transcriptionally coordinating two critical processes for GABA neurotransmission. Further, we uncover multiple target genes and a dual role for UNC-30 both as an activator and repressor of gene transcription. Our findings on UNC-30 function may contribute to our molecular understanding of human conditions, such as Axenfeld-Rieger syndrome, caused by PITX2 and PITX3 gene mutations.