{"database":"biostudies-literature","file_versions":[],"scores":null,"additional":{"submitter":["Iguchi T"],"funding":["Japan Society for the Promotion of Science"],"pagination":["4795-4808"],"full_dataset_link":["https://www.ebi.ac.uk/biostudies/studies/S-EPMC8260171"],"repository":["biostudies-literature"],"omics_type":["Unknown"],"volume":["41(22)"],"pubmed_abstract":["Coordination of skilled movements and motor planning relies on the formation of regionally restricted brain circuits that connect cortex with subcortical areas during embryonic development. Layer 5 neurons that are distributed across most cortical areas innervate the pontine nuclei (basilar pons) by protrusion and extension of collateral branches interstitially along their corticospinal extending axons. Pons-derived chemotropic cues are known to attract extending axons, but molecules that regulate collateral extension to create regionally segregated targeting patterns have not been identified. Here, we discovered that <i>EphA7</i> and <i>EfnA5</i> are expressed in the cortex and the basilar pons in a region-specific and mutually exclusive manner, and that their repulsive activities are essential for segregating collateral extensions from corticospinal axonal tracts in mice. Specifically, <i>EphA7</i> and <i>EfnA5</i> forward and reverse inhibitory signals direct collateral extension such that <i>EphA7</i>-positive frontal and occipital cortical areas extend their axon collaterals into the <i>EfnA5</i>-negative rostral part of the basilar pons, whereas <i>EfnA5</i>-positive parietal cortical areas extend their collaterals into the <i>EphA7</i>-negative caudal part of the basilar pons. Together, our results provide a molecular basis that explains how the corticopontine projection connects multimodal cortical outputs to their subcortical targets.<b>SIGNIFICANCE STATEMENT</b> Our findings put forward a model in which region-to-region connections between cortex and subcortical areas are shaped by mutually exclusive molecules to ensure the fidelity of regionally restricted circuitry. This model is distinct from earlier work showing that neuronal circuits within individual cortical modalities form in a topographical manner controlled by a gradient of axon guidance molecules. The principle that a shared molecular program of mutually repulsive signaling instructs regional organization-both within each brain region and between connected brain regions-may well be applicable to other contexts in which information is sorted by converging and diverging neuronal circuits."],"journal":["The Journal of neuroscience : the official journal of the Society for Neuroscience"],"pubmed_title":["Mutually Repulsive EphA7-EfnA5 Organize Region-to-Region Corticopontine Projection by Inhibiting Collateral Extension."],"pmcid":["PMC8260171"],"funding_grant_id":["JSPS KAKENHI 19K22471","JSPS KAKENHI 21390052","JSPS KAKENHI 26430036","JSPS KAKENHI 19K06923","JSPS KAKENHI 25293043","JSPS KAKENHI 17H04014","JSPS KAKENHI 24700323","JSPS KAKENHI 26430017"],"pubmed_authors":["Yasumura M","Bastmeyer M","Iguchi T","Omi M","Yagi H","Oka Y","Taniguchi M","Xie MJ","Sato M","Kuroda K"],"additional_accession":[]},"is_claimable":false,"name":"Mutually Repulsive EphA7-EfnA5 Organize Region-to-Region Corticopontine Projection by Inhibiting Collateral Extension.","description":"Coordination of skilled movements and motor planning relies on the formation of regionally restricted brain circuits that connect cortex with subcortical areas during embryonic development. Layer 5 neurons that are distributed across most cortical areas innervate the pontine nuclei (basilar pons) by protrusion and extension of collateral branches interstitially along their corticospinal extending axons. Pons-derived chemotropic cues are known to attract extending axons, but molecules that regulate collateral extension to create regionally segregated targeting patterns have not been identified. Here, we discovered that <i>EphA7</i> and <i>EfnA5</i> are expressed in the cortex and the basilar pons in a region-specific and mutually exclusive manner, and that their repulsive activities are essential for segregating collateral extensions from corticospinal axonal tracts in mice. Specifically, <i>EphA7</i> and <i>EfnA5</i> forward and reverse inhibitory signals direct collateral extension such that <i>EphA7</i>-positive frontal and occipital cortical areas extend their axon collaterals into the <i>EfnA5</i>-negative rostral part of the basilar pons, whereas <i>EfnA5</i>-positive parietal cortical areas extend their collaterals into the <i>EphA7</i>-negative caudal part of the basilar pons. Together, our results provide a molecular basis that explains how the corticopontine projection connects multimodal cortical outputs to their subcortical targets.<b>SIGNIFICANCE STATEMENT</b> Our findings put forward a model in which region-to-region connections between cortex and subcortical areas are shaped by mutually exclusive molecules to ensure the fidelity of regionally restricted circuitry. This model is distinct from earlier work showing that neuronal circuits within individual cortical modalities form in a topographical manner controlled by a gradient of axon guidance molecules. The principle that a shared molecular program of mutually repulsive signaling instructs regional organization-both within each brain region and between connected brain regions-may well be applicable to other contexts in which information is sorted by converging and diverging neuronal circuits.","dates":{"release":"2021-01-01T00:00:00Z","publication":"2021 Jun","modification":"2025-04-04T19:50:05.454Z","creation":"2022-02-11T13:29:06.765Z"},"accession":"S-EPMC8260171","cross_references":{"pubmed":["33906900"],"doi":["10.1523/JNEUROSCI.0367-20.2021","10.1523/jneurosci.0367-20.2021"]}}