PTPRO restricts higher-order branching of terminal arbors through TrkB dephosphorylation

The structural complexity of axon collateral terminal arbors shapes synaptic connectivity. In corticospinal projections, individual axon collaterals exhibit distinct patterns of terminal arborization, ranging from sparse local branches to dense, highly complex arbors in target regions such as the pontine nuclei. How this complexity is controlled remains poorly understood. Here, using corticopontine projections in male and female mice, we show that protein tyrosine phosphatase receptor type O (PTPRO) selectively restricts higher-order branching of terminal arbors in the pontine nuclei without affecting collateral number. This function requires the intracellular phosphatase domain of PTPRO but not its extracellular region. We demonstrate that PTPRO dephosphorylates tropomyosin receptor kinase B (TrkB), and that the excessive terminal arborization caused by acute PTPRO loss is rescued by TrkB depletion or phosphatidylinositol 3-kinase (PI3K) inhibition. Together, these findings reveal that PTPRO-mediated TrkB dephosphorylation acts as a molecular brake on corticopontine terminal arbor elaboration. Significance Statement How individual axons regulate terminal branching within target regions is a fundamental question in neural circuit development. This study identifies protein tyrosine phosphatase receptor type O (PTPRO), a receptor-type protein tyrosine phosphatase that negatively regulates signaling through tyrosine phosphorylation, as a selective regulator of higher-order branching in corticopontine terminal arbors. PTPRO dephosphorylates tropomyosin receptor kinase B (TrkB), a neurotrophin receptor tyrosine kinase that promotes neuronal growth and branching, thereby restricting terminal arbor complexity without affecting collateral number from the main axon. Given that terminal arbor architecture determines the synaptic territory of each cortical input, PTPRO-dependent constraint on arbor elaboration may represent a general principle by which projection-specific arbor complexity is established across long-range circuits in the central nervous system.