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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]

The molecular code that controls synapse formation and maintenance in vivo has remained quite sparse. Here, we identify that the secreted protein Adamtsl3 functions as critical hippocampal synapse organizer acting through the transmembrane receptor DCC (deleted in colorectal cancer). Traditionally, DCC function has been associated with glutamatergic synaptogenesis and plasticity in response to Netrin-1 signaling. We demonstrate that early post-natal deletion of Adamtsl3 in neurons impairs DCC protein expression, causing reduced density of both glutamatergic and GABAergic synapses. Adult deletion of Adamtsl3 in either GABAergic or glutamatergic neurons does not interfere with DCC-Netrin-1 function at glutamatergic synapses but controls DCC signaling at GABAergic synapses. The Adamtsl3-DCC signaling unit is further essential for activity-dependent adaptations at GABAergic synapses, involving DCC phosphorylation and Src kinase activation. These findings might be particularly relevant for schizophrenia because genetic variants in Adamtsl3 and DCC have been independently linked with schizophrenia in patients. [Display omitted] • Adamtsl3 is widely expressed at hippocampal synapses • Adamtsl3 is a ligand for DCC during synaptogenesis and in the mature brain • Presynaptic and postsynaptic Adamtsl3 contribute toward GABAergic synapse maintenance via DCC • Autocrine Adamtsl3-DCC signaling mediates plasticity adaptations at GABAergic postsynapse The secreted glycoprotein Ce-Punctin clusters neurotransmitter receptors at the C. elegans NMJ. Cramer et al. reveal that Ce-Punctin ortholog Adamtsl3 is a synaptic protein influencing synapse formation via the DCC receptor in the mouse brain. In the adult hippocampus, Adamtsl3-DCC signaling specializes toward GABAergic synapse function with behavioral consequences. [ABSTRACT FROM AUTHOR]

A critical accomplishment in the rapidly developing field of regenerative medicine will be the ability to foster repair of neurons severed by injury, disease, or microsurgery. In C. elegans, individual visualized axons can be laser-cut in vivo and neuronal responses to damage can be monitored to decipher genetic requirements for regeneration. With an initial interest in how local environments manage cellular debris, we performed femtosecond laser axotomies in genetic backgrounds lacking cell death gene activities. Unexpectedly, we found that the CED-3 caspase, well known as the core apoptotic cell death executioner, acts in early responses to neuronal injury to promote rapid regeneration of dissociated axons. In ced-3 mutants, initial regenerative outgrowth dynamics are impaired and axon repair through reconnection of the two dissociated ends is delayed. The CED-3 activator, CED-4/Apaf-1, similarly promotes regeneration, but the upstream regulators of apoptosis CED-9/Bcl2 and BH3-domain proteins EGL-1 and CED-13 are not essential. Thus, a novel regulatory mechanism must be utilized to activate core apoptotic proteins for neuronal repair. Since calcium plays a conserved modulatory role in regeneration, we hypothesized calcium might play a critical regulatory role in the CED-3/CED-4 repair pathway. We used the calcium reporter cameleon to track in vivo calcium fluxes in the axotomized neuron. We show that when the endoplasmic reticulum calcium-storing chaperone calreticulin, CRT-1, is deleted, both calcium dynamics and initial regenerative outgrowth are impaired. Genetic data suggest that CED-3, CED-4, and CRT-1 act in the same pathway to promote early events in regeneration and that CED-3 might act downstream of CRT-1, but upstream of the conserved DLK-1 kinase implicated in regeneration across species. This study documents reconstructive roles for proteins known to orchestrate apoptotic death and links previously unconnected observations in the vertebrate literature to suggest a similar pathway may be conserved in higher organisms. [ABSTRACT FROM AUTHOR]