RESUMO
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 cord motor 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.
Assuntos
Proteínas de Caenorhabditis elegans , Caenorhabditis elegans , Neurônios Motores , Fatores de Transcrição , Animais , Caenorhabditis elegans/metabolismo , Caenorhabditis elegans/genética , Proteínas de Caenorhabditis elegans/metabolismo , Proteínas de Caenorhabditis elegans/genética , Ácido gama-Aminobutírico/metabolismo , Proteínas de Homeodomínio/metabolismo , Proteínas de Homeodomínio/genética , Neurônios Motores/metabolismo , Proteínas do Tecido Nervoso , Neurotransmissores/metabolismo , Receptores de GABA/metabolismo , Receptores de GABA/genética , Receptores de GABA-A/metabolismo , Receptores de GABA-A/genética , Sinapses/metabolismo , Transmissão Sináptica , Fatores de Transcrição/metabolismo , Fatores de Transcrição/genética , Proteínas Nucleares/genética , Proteínas Nucleares/metabolismoRESUMO
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.