During mammalian development, retinal ganglion cell (RGC) axons from nasal retina cross the optic chiasm midline, whereas temporal retina axons do not and grow ipsilaterally, resulting in a projection of part of the visual world onto one side of the brain while the remaining part is represented on the opposite side. Previous studies have shown that RGC axons in GAP-43-deficient mice initially fail to grow from the optic chiasm to form optic tracts and are delayed temporarily in the midline region. Here we show that this delayed RGC axon exit from the chiasm is characterized by abnormal randomized axon routing into the ipsilateral and contralateral optic tracts, leading to duplicated representations of the visual world in both sides of the brain. Within the chiasm, individual contralaterally projecting axons grow in unusual semicircular trajectories, and the normal ipsilateral turning of ventral temporal axons is absent. These effects on both axon populations suggest that GAP-43 does not mediate pathfinding...

Canonical and noncanonical Wnt signaling pathways are essential for development and maintenance of the CNS. Whereas the roles of canonical Wnt pathways in neuronal survival and axonal regeneration in adult CNS have been described, the functions of noncanonical Wnt pathways are not well understood. Furthermore, the role of noncanonical Wnt ligands in the adult retina has not been investigated. Noncanonical Wnt signaling shares receptors with canonical Wnt ligands but functions through calcium and c-Jun N-terminal kinase (JNK) signaling pathways. Noncanonical ligands, such as the prototypic ligand Wnt5a, have varying effects in the developing CNS, including inhibiting or promoting axonal growth. To identify a role for noncanonical Wnt signaling in the developed retina after injury, we characterized the effect of Wnt5a on neurite outgrowth in cultured retinal ganglion cell (RGC) neurons and on axonal regeneration in the injured optic nerve in the mouse. Endogenous Wnt5a was upregulated after injury and exogen...

Axon branching plays a critical role in establishing the accurate patterning of neuronal circuits in the brain. However, the mechanisms that control axon branching remain poorly understood. Here we report that knockdown of the brain-enriched signaling protein JNK-interacting protein 3 (JIP3) triggers exuberant axon branching and self-contact in primary granule neurons of the rat cerebellar cortex. JIP3 knockdown in cerebellar slices and in postnatal rat pups in vivo leads to the formation of ectopic branches in granule neuron parallel fiber axons in the cerebellar cortex. We also find that JIP3 restriction of axon branching is mediated by the protein kinase glycogen synthase kinase 3β (GSK3β). JIP3 knockdown induces the downregulation of GSK3β in neurons, and GSK3β knockdown phenocopies the effect of JIP3 knockdown on axon branching and self-contact. Finally, we establish doublecortin (DCX) as a novel substrate of GSK3β in the control of axon branching and self-contact. GSK3β phosphorylates DCX at the dist...

The classical view of neurons emphasizes the role of dendrites for synaptic signal integration and plasticity. In contrast, the axon has been recognized as a rather static output device. This view is rapidly changing, with recent research revealing a mu...

Despite of the fact that peripheral nerve can regenerate, clinical outcomes after peripheral nerve injuries (PNI) are still unsatisfactory, especially in severe and proximal injury cases. Accumulated evidences show that Schwann cell (SC) graft is one of...

Spinal cord injury (SCI) is a devastating trauma leading to widespread disruption of motor, sensory, and physiological functions, including an-ejaculation in >85% of SCI patients. Regaining sexual function is of high priority to SCI patients. Ejaculatio...

The axon initial segment (AIS) is the site of action potential initiation and serves as a diffusion barrier that helps maintain neuronal polarity. Recent studies have revealed details about a specialized structural complex in the AIS. The specific role ...

Leucine-rich repeat kinase 2 (LRRK2), a multi-domain protein, is a one of the causal factors in Parkinson’s disease. Numerous studies revealed that LRRK2 regulates membrane trafficking, including synaptic vesicle endocytosis. We discovered a novel funct...

Oligodendrocytes (OLs), myelinating cells in the central nervous system (CNS), facilitate the rapid propagation of action potential and the formation of neural precise networks. The interaction of OLs with axons is essential for myelination, and its abn...

The breast cancer susceptibility protein BRCA1 and its partner BRCA1-associated RING domain protein 1 (BARD1) form an E3-ubiquitin (Ub) ligase complex that acts as a tumor suppressor in mitotic cells. However, the roles of BRCA1–BARD1 in postmitotic cells, such as neurons, remain poorly defined. Here, we report that BRC-1 and BRD-1, the Caenorhabditis elegans orthologs of BRCA1 and BARD1, are required for adult-specific axon regeneration, which is positively regulated by the EGL-30 Gqα–diacylglycerol (DAG) signaling pathway. This pathway is downregulated by DAG kinase (DGK), which converts DAG to phosphatidic acid (PA). We demonstrate that inactivation of DGK-3 suppresses the brc-1 brd-1 defect in axon regeneration, suggesting that BRC-1–BRD-1 inhibits DGK-3 function. Indeed, we show that BRC-1–BRD-1 poly-ubiquitylates DGK-3 in a manner dependent on its E3 ligase activity, causing DGK-3 degradation. Furthermore, we find that axon injury causes the translocation of BRC-1 from the nucleus to the cytoplasm, w...