Xue Yan Ho

All Publications

• Stochastic growth and ligand-receptor interaction-mediated stabilization generate stereotyped dendritic arbors. Nature neuroscience Shi, R., Ho, X. Y., Tao, L., Bayless-Edwards, L., Taylor, C. A., Zhao, T., Zou, W., Lizzappi, M., Eichel, K., Mao, T., Shen, K. 2026

  Abstract

  Stereotyped dendritic arbors are shaped by dynamic and stochastic growth during neuronal development. It remains unclear how guidance receptors and ligands coordinate branch dynamic growth, retraction and stabilization to specify dendritic arbors. We previously showed that extracellular adhesion ligand SAX-7/LICAM dictates the elaborate and stereotyped shape of the Caenorhabditis elegans PVD sensory dendrite via binding to the guidance receptor DMA-1, a single transmembrane adhesion molecule. Here, we perform structure-function analyses of DMA-1 and unexpectedly find that robust, stochastic dendritic growth does not require ligand binding. Instead, ligand contacts prevent dendrite retraction, inhibit ectopic growth and specify arbor shape. Furthermore, we demonstrate that dendritic growth requires a pool of ligand-free DMA-1, which is maintained by receptor endocytosis and reinsertion to the plasma membrane via recycling endosomes. Mutants defective of DMA-1 endocytosis show severely truncated dendrites. We present a model in which ligand-free guidance receptor mediates intrinsic, stochastic dendritic growth, while extracellular ligands instruct dendrite shape by inhibiting growth.

  View details for DOI 10.1038/s41593-026-02278-0

  View details for PubMedID 42082815

  View details for PubMedCentralID 4299270

• The dynamin GTPase mediates regenerative axonal fusion in Caenorhabditis elegans by regulating fusogen levels PNAS NEXUS Vijayaraghavan, T., Dhananjay, S., Ho, X., Giordano-Santini, R., Hilliard, M., Neumann, B. 2023; 2 (5): pgad114

  Abstract

  Axonal fusion is a neuronal repair mechanism that results in the reconnection of severed axon fragments, leading to the restoration of cytoplasmic continuity and neuronal function. While synaptic vesicle recycling has been linked to axonal regeneration, its role in axonal fusion remains unknown. Dynamin proteins are large GTPases that hydrolyze lipid-binding membranes to carry out clathrin-mediated synaptic vesicle recycling. Here, we show that the Caenorhabditis elegans dynamin protein DYN-1 is a key component of the axonal fusion machinery. Animals carrying a temperature-sensitive allele of dyn-1(ky51) displayed wild-type levels of axonal fusion at the permissive temperature (15°C) but presented strongly reduced levels at the restrictive temperature (25°C). Furthermore, the average length of regrowth was significantly diminished in dyn-1(ky51) animals at the restrictive temperature. The expression of wild-type DYN-1 cell-autonomously into dyn-1(ky51) mutant animals rescued both the axonal fusion and regrowth defects. Furthermore, DYN-1 was not required prior to axonal injury, suggesting that it functions specifically after injury to control axonal fusion. Finally, using epistatic analyses and superresolution imaging, we demonstrate that DYN-1 regulates the levels of the fusogen protein EFF-1 post-injury to mediate axonal fusion. Together, these results establish DYN-1 as a novel regulator of axonal fusion.

  View details for DOI 10.1093/pnasnexus/pgad114

  View details for Web of Science ID 001053144200026

  View details for PubMedID 37181046

  View details for PubMedCentralID PMC10167995

• The metalloprotease ADM-4/ADAM17 promotes axonal repair SCIENCE ADVANCES Ho, X., Coakley, S., Amor, R., Anggono, V., Hilliard, M. A. 2022; 8 (11): eabm2882

  Abstract

  Axonal fusion is an efficient means of repair following axonal transection, whereby the regenerating axon fuses with its own separated axonal fragment to restore neuronal function. Despite being described over 50 years ago, its molecular mechanisms remain poorly understood. Here, we demonstrate that the Caenorhabditis elegans metalloprotease ADM-4, an ortholog of human ADAM17, is essential for axonal fusion. We reveal that animals lacking ADM-4 cannot repair their axons by fusion, and that ADM-4 has a cell-autonomous function within injured neurons, localizing at the tip of regrowing axon and fusion sites. We demonstrate that ADM-4 overexpression enhances fusion to levels higher than wild type, and that the metalloprotease and phosphatidylserine-binding domains are essential for its function. Last, we show that ADM-4 interacts with and stabilizes the fusogen EFF-1 to allow membranes to merge. Our results uncover a key role for ADM-4 in axonal fusion, exposing a molecular target for axonal repair.

  View details for DOI 10.1126/sciadv.abm2882

  View details for Web of Science ID 000770280500010

  View details for PubMedID 35294233

  View details for PubMedCentralID PMC8926332

• Disruption of RAB-5 Increases EFF-1 Fusogen Availability at the Cell Surface and Promotes the Regenerative Axonal Fusion Capacity of the Neuron JOURNAL OF NEUROSCIENCE Linton, C., Riyadh, M., Ho, X., Neumann, B., Giordano-Santini, R., Hilliard, M. A. 2019; 39 (15): 2823-2836

  Abstract

  Following a transection injury to the axon, neurons from a number of species have the ability to undergo spontaneous repair via fusion of the two separated axonal fragments. In the nematode Caenorhabditis elegans, this highly efficient regenerative axonal fusion is mediated by epithelial fusion failure-1 (EFF-1), a fusogenic protein that functions at the membrane to merge the two axonal fragments. Identifying modulators of axonal fusion and EFF-1 is an important step toward a better understanding of this repair process. Here, we present evidence that the small GTPase RAB-5 acts to inhibit axonal fusion, a function achieved via endocytosis of EFF-1 within the injured neuron. Therefore, we find that perturbing RAB-5 activity is sufficient to restore axonal fusion in mutant animals with decreased axonal fusion capacity. This is accompanied by enhanced membranous localization of EFF-1 and the production of extracellular EFF-1-containing vesicles. These findings identify RAB-5 as a novel regulator of axonal fusion in C. elegans hermaphrodites and the first regulator of EFF-1 in neurons.SIGNIFICANCE STATEMENT Peripheral and central nerve injuries cause life-long disabilities due to the fact that repair rarely leads to reinnervation of the target tissue. In the nematode Caenorhabditis elegans, axonal regeneration can proceed through axonal fusion, whereby a regrowing axon reconnects and fuses with its own separated distal fragment, restoring the original axonal tract. We have characterized axonal fusion and established that the fusogen epithelial fusion failure-1 (EFF-1) is a key element for fusing the two separated axonal fragments back together. Here, we show that the small GTPase RAB-5 is a key cell-intrinsic regulator of the fusogen EFF-1 and can in turn regulate axonal fusion. Our findings expand the possibility for this process to be controlled and exploited to facilitate axonal repair in medical applications.

  View details for DOI 10.1523/JNEUROSCI.1952-18.2019

  View details for Web of Science ID 000463987700004

  View details for PubMedID 30737314

  View details for PubMedCentralID PMC6462446

• Oxidative stress promotes SIRT1 recruitment to the GADD34/PP1α complex to activate its deacetylase function CELL DEATH AND DIFFERENTIATION Lee, I., Ho, X., George, S., Goh, C., Sundaram, J., Pang, K., Luo, W., Yusoff, P., Sze, N., Shenolikar, S. 2018; 25 (2): 255-267

  Abstract

  Phosphorylation of the eukaryotic translation initiation factor, eIF2α, by stress-activated protein kinases and dephosphorylation by the growth arrest and DNA damage-inducible protein (GADD34)-containing phosphatase is a central node in the integrated stress response. Mass spectrometry demonstrated GADD34 acetylation at multiple lysines. Substituting K315 and K322 with alanines or glutamines did not impair GADD34's ability to recruit protein phosphatase 1α (PP1α) or eIF2α, suggesting that GADD34 acetylation did not modulate eIF2α phosphatase activity. Arsenite (Ars)-induced oxidative stress increased cellular GADD34 levels and enhanced Sirtuin 1 (SIRT1) recruitment to assemble a cytoplasmic complex containing GADD34, PP1α, eIF2α and SIRT1. Induction of GADD34 in WT MEFs paralleled the dephosphorylation of eIF2α (phosphoserine-51) and SIRT1 (phosphoserine-47). By comparison, eIF2α and SIRT1 were persistently phosphorylated in Ars-treated GADD34-/- MEFs. Expressing WT GADD34, but not a mutant unable to bind PP1α in GADD34-/- MEFs restored both eIF2α and SIRT1 dephosphorylation. SIRT1 dephosphorylation increased its deacetylase activity, measured in vitro and in cells. Loss of function of GADD34 or SIRT1 enhanced cellular p-eIF2α levels and attenuated cell death following Ars exposure. These results highlighted a novel role for the GADD34/PP1α complex in coordinating the dephosphorylation and reactivation of eIF2α and SIRT1 to determine cell fate following oxidative stress.

  View details for DOI 10.1038/cdd.2017.152

  View details for Web of Science ID 000424342100003

  View details for PubMedID 28984870

  View details for PubMedCentralID PMC5762841

• 6-OHDA-induced dopaminergic neurodegeneration in <i>Caenorhabditis elegans</i> is promoted by the engulfment pathway and inhibited by the transthyretin-related protein TTR-33 PLOS GENETICS Offenburger, S., Ho, X., Tachie-Menson, T., Coakley, S., Hilliard, M. A., Gartner, A. 2018; 14 (1): e1007125

  Abstract

  Oxidative stress is linked to many pathological conditions including the loss of dopaminergic neurons in Parkinson's disease. The vast majority of disease cases appear to be caused by a combination of genetic mutations and environmental factors. We screened for genes protecting Caenorhabditis elegans dopaminergic neurons from oxidative stress induced by the neurotoxin 6-hydroxydopamine (6-OHDA) and identified the transthyretin-related gene ttr-33. The only described C. elegans transthyretin-related protein to date, TTR-52, has been shown to mediate corpse engulfment as well as axon repair. We demonstrate that TTR-52 and TTR-33 have distinct roles. TTR-33 is likely produced in the posterior arcade cells in the head of C. elegans larvae and is predicted to be a secreted protein. TTR-33 protects C. elegans from oxidative stress induced by paraquat or H2O2 at an organismal level. The increased oxidative stress sensitivity of ttr-33 mutants is alleviated by mutations affecting the KGB-1 MAPK kinase pathway, whereas it is enhanced by mutation of the JNK-1 MAPK kinase. Finally, we provide genetic evidence that the C. elegans cell corpse engulfment pathway is required for the degeneration of dopaminergic neurons after exposure to 6-OHDA. In summary, we describe a new neuroprotective mechanism and demonstrate that TTR-33 normally functions to protect dopaminergic neurons from oxidative stress-induced degeneration, potentially by acting as a secreted sensor or scavenger of oxidative stress.

  View details for DOI 10.1371/journal.pgen.1007125

  View details for Web of Science ID 000423718600004

  View details for PubMedID 29346382

  View details for PubMedCentralID PMC5773127