PUBLICATIONS

For a full list of publications from our lab, visit Dr. Fu’s Google Scholar page.

preprints

  • https://www.biorxiv.org/content/10.64898/2025.12.23.696264v1

    Authors: Nowacki JC, Bulen HL, Meservey LM, Richardson H, Valenzuela A, Nguyen H, Cheng Z, Zeng H, Fu MM

    Abstract:
    Myelin sheath maturation requires compaction, a cellular phenomenon mediated by local translation of myelin basic protein (MBP), which acts as a molecular zipper to join adjacent membranes and extrude the cytoplasm. Contrary to decades-old microinjection experiments indicating that Mbp mRNA transport is restricted to microtubules, we now show using smFISH that endogenous Mbp mRNA granules indeed localize along actin. To validate the in vivo necessity of Mbp mRNA transport and its dependence on the 3’ UTR (untranslated region), we replaced the endogenous Mbp 3’ UTR with polyA tail sequences. Though these mice have decreased Mbp mRNA levels, this alone could not account for their striking phenotypes – hypomyelination, baseline tremors, and motor learning defects. Thus, we cultured oligodendrocytes from these mice and found defects in both Mbp mRNA localization and local translation. These results demonstrate that the 3’ UTR of a locally translated structural protein is critical for both developmental and activity-induced myelination.

  • https://www.biorxiv.org/content/10.1101/2025.11.19.689361v1

    Authors: Topkar VV, Wu V, Ho LT, Ambiel N, Valenzuela A, Yoshimura K, Zuchero JB, Fu MM [co-corresponding], Das R

    Abstract:
    Oligodendrocytes myelinate the central nervous system by extending cellular projections that ensheath axons and elongate to form lipid-rich myelin. Classic studies visualizing RNA dynamics showed that myelin basic protein (MBP), one of the most abundant myelin proteins, is locally synthesized at the myelin sheath through the transport and local translation of Mbp mRNA. Mbp transport requires its 1.5-kb 3' untranslated region (3' UTR) and prior work identified candidate sub-sequences that may act as cis-acting transport stimulating RNA elements, including one with putative secondary structure. Here, a high-throughput reporter assay, dimethyl sulfate (DMS)-based RNA structure probing, and microscopy in primary rat oligodendrocytes identify a structured 127-nt region that we name the Mbp localization signal (MLS) as both necessary and sufficient for RNA enrichment to oligodendrocyte projections. Lysate pulldown experiments further identify hnRNP-F — a known constituent of the Mbp RNA granule that can suppress mRNA translation — as associated with the MLS; paradoxically, binding of this protein should compete with the ordered MLS RNA structure. These results suggest a model in which the MLS switches between two RNA conformations with distinct protein partners during the transition from Mbp mRNA transport to Mbp translation at the myelin sheath. Such regulation of RNA behavior by structure switching may generalize to other eukaryotic mRNAs whose behaviors shift across space and time.

  • https://www.biorxiv.org/content/10.1101/2025.10.10.681734v1

    Authors: Wynne ME, Barclay WE, Gopal D, Bergstrom JJ, Ho LT, Lopez EA, Nogales E, Fu MM

    Abstract:
    Astrocytes, the most abundant cells in the brain, extend elaborate branches that enable diverse functions, from synapse maintenance to blood-brain-barrier integrity. The cytoskeletal basis of this architecture has remained unclear, since traditional culturing methods produce minimal branching. Using immunopanning and serum-free conditions, we generated primary rodent astrocytes with in-vivo–like morphology and surveyed their cytoskeleton using confocal microscopy and cryogenic electron tomography. We show that astrocyte microtubules are oriented primarily plus-ends–out. Proximally, microtubules appear stabilized by post-translational modifications (PTMs) and microtubule inner proteins (MIPs). Distal regions lack stabilizing microtubule PTMs, and are enriched in intermediate filament (IF) GFAP. Additionally, diverse actin microstructures, including reticular webbing, extend astrocyte boundaries beyond the microtubule–IF framework. Our results uncover fundamental principles of astrocyte cytoskeletal organization that underlie their intricate branching.

  • https://www.biorxiv.org/content/10.1101/2023.05.31.542915v1

    Authors: Kemal S, Richardson HS, McAlear TS, Kopach A, Nowacki JC, Li Y, Bechstedt S, Fu MM

    Abstract:
    Oligodendrocytes have elaborate arbors of microtubules that extend toward axons and spiral around myelin sheaths. Oligodendrocytes rely on satellite organelles called Golgi outposts to nucleate new microtubules at sites far from the cell body. We now show that the Golgi outpost marker TPPP (tubulin polymerization promoting protein) forms liquid condensates that co-partition with tubulin in order to nucleate microtubules. In oligodendrocytes, TPPP forms either dynamic puncta or aberrant microtubule-associated aggregates. In Multiple System Atrophy (MSA), a sequela of histological events initiates with TPPP aggregation in myelin sheaths and terminates in perinuclear TPPP co-aggregation with alpha-synuclein (aSyn). Finally, recombinant TPPP aggregates are toxic to primary oligodendrocytes. Thus, while the liquid condensate property of TPPP facilitates microtubule nucleation, it also predisposes TPPP to aggregate in disease.

collaborations

  • https://pubmed.ncbi.nlm.nih.gov/38826296/

    Nat Commun. 2025 Mar 7;16(1):2283.

    Authors: Gross PS, Durán-Laforet V, Ho LT, Melchor GS, Zia S, Manavi Z, Barclay WE, Lee SH, Shults N, Selva S, Alvarez E, Plemel JR, Fu MM, Schafer DP, Huang JK.

    Abstract:
    The capacity to regenerate myelin in the central nervous system (CNS) diminishes with age. This decline is particularly evident in multiple sclerosis (MS), which has been suggested to exhibit features of accelerated biological aging. Whether cellular senescence, a hallmark of aging, contributes to remyelination impairment remains unknown. Here, we show that senescent cells (SCs) accumulate within demyelinated lesions after injury, and their elimination enhances remyelination in young mice but not in aged mice. In young mice, we observed the upregulation of senescence-associated transcripts primarily in microglia after demyelination, followed by their reduction during remyelination. However, in aged mice, senescence-associated factors persisted within lesions, correlating with inefficient remyelination. We found that SC elimination enhanced remyelination in young mice but was ineffective in aged mice. Proteomic analysis of senescence-associated secretory phenotype (SASP) revealed elevated levels of CCL11/Eotaxin-1 in lesions, which was found to inhibit efficient oligodendrocyte maturation. These results suggest therapeutic targeting of SASP components, such as CCL11, may improve remyelination in aging and MS.

  • https://pubmed.ncbi.nlm.nih.gov/38167866/

    NPJ Regen Med. 2024 Jan 2;9(1):1.

    Authors: Hu J, Melchor GS, Ladakis D, Reger J, Kim HW, Chamberlain KA, Shults NV, Oft HC, Smith VN, Rosko LM, Li E, Baydyuk M, Fu MM, Bhargava P, Huang JK

    Abstract:
    Regulation of myeloid cell activity is critical for successful myelin regeneration (remyelination) in demyelinating diseases, such as multiple sclerosis (MS). Here, we show aromatic alpha-keto acids (AKAs) generated from the amino acid oxidase, interleukin-4 induced 1 (IL4I1), promote efficient remyelination in mouse models of MS. During remyelination, myeloid cells upregulated the expression of IL4I1. Conditionally knocking out IL4I1 in myeloid cells impaired remyelination efficiency. Mice lacking IL4I1 expression exhibited a reduction in the AKAs, phenylpyruvate, indole-3-pyruvate, and 4-hydroxyphenylpyruvate, in remyelinating lesions. Decreased AKA levels were also observed in people with MS, particularly in the progressive phase when remyelination is impaired. Oral administration of AKAs modulated myeloid cell-associated inflammation, promoted oligodendrocyte maturation, and enhanced remyelination in mice with focal demyelinated lesions. Transcriptomic analysis revealed AKA treatment induced a shift in metabolic pathways in myeloid cells and upregulated aryl hydrocarbon receptor activity in lesions. Our results suggest myeloid cell-associated aromatic amino acid metabolism via IL4I1 produces AKAs in demyelinated lesions to enable efficient remyelination. Increasing AKA levels or targeting related pathways may serve as a strategy to facilitate the regeneration of myelin in inflammatory demyelinating conditions.

  • https://pubmed.ncbi.nlm.nih.gov/34812142/

    Elife. 2021 Nov 23:10:e69815.

    Authors: Creighton BA, Afriyie S, Ajit D, Casingal CR, Voos KM, Reger J, Burch AM, Dyne E, Bay J, Huang JK, Anton ES, Fu MM, Lorenzo DN

    Abstract:
    Variants in the high confident autism spectrum disorder (ASD) gene ANK2 target both ubiquitously expressed 220 kDa ankyrin-B and neurospecific 440 kDa ankyrin-B (AnkB440) isoforms. Previous work showed that knock-in mice expressing an ASD-linked Ank2 variant yielding a truncated AnkB440 product exhibit ectopic brain connectivity and behavioral abnormalities. Expression of this variant or loss of AnkB440 caused axonal hyperbranching in vitro, which implicated AnkB440 microtubule bundling activity in suppressing collateral branch formation. Leveraging multiple mouse models, cellular assays, and live microscopy, we show that AnkB440 also modulates axon collateral branching stochastically by reducing the number of F-actin-rich branch initiation points. Additionally, we show that AnkB440 enables growth cone (GC) collapse in response to chemorepellent factor semaphorin 3 A (Sema 3 A) by stabilizing its receptor complex L1 cell adhesion molecule/neuropilin-1. ASD-linked ANK2 variants failed to rescue Sema 3A-induced GC collapse. We propose that impaired response to repellent cues due to AnkB440 deficits leads to axonal targeting and branch pruning defects and may contribute to the pathogenicity of ANK2 variants.

key papers

  • https://pubmed.ncbi.nlm.nih.gov/31522887/

    Authors: Fu MM, McAlear TS, Nguyen H, Oses-Prieto JA, Valenzuela A, Shi RD, Perrino JJ, Huang TT, Burlingame AL, Bechstedt S, Barres BA

    Abstract:
    Astrocytes, the most abundant cells in the brain, extend elaborate branches that enable diverse functions, from synapse maintenance to blood-brain-barrier integrity. The cytoskeletal basis of this architecture has remained unclear, since traditional culturing methods produce minimal branching. Using immunopanning and serum-free conditions, we generated primary rodent astrocytes with in-vivo–like morphology and surveyed their cytoskeleton using confocal microscopy and cryogenic electron tomography. We show that astrocyte microtubules are oriented primarily plus-ends–out. Proximally, microtubules appear stabilized by post-translational modifications (PTMs) and microtubule inner proteins (MIPs). Distal regions lack stabilizing microtubule PTMs, and are enriched in intermediate filament (IF) GFAP. Additionally, diverse actin microstructures, including reticular webbing, extend astrocyte boundaries beyond the microtubule–IF framework. Our results uncover fundamental principles of astrocyte cytoskeletal organization that underlie their intricate branching.

  • https://pubmed.ncbi.nlm.nih.gov/29073112/

    PNAS. 2017 Oct 24;114(43):E9153-E9162.

    Authors: Herbert AL, Fu MM [co-first, co-corr], Drerup CM, Gray RS, Harty BL, Ackerman SD, O’Reilly-Pol T, Johnson SL, Nechiporuk AV, Barres BA, Monk KR

    Abstract:
    Oligodendrocytes in the central nervous system produce myelin, a lipid-rich, multilamellar sheath that surrounds axons and promotes the rapid propagation of action potentials. A critical component of myelin is myelin basic protein (MBP), expression of which requires anterograde mRNA transport followed by local translation at the developing myelin sheath. Although the anterograde motor kinesin KIF1B is involved in mbp mRNA transport in zebrafish, it is not entirely clear how mbptransport is regulated. From a forward genetic screen for myelination defects in zebrafish, we identified a mutation in actr10, which encodes the Arp11 subunit of dynactin, a critical activator of the retrograde motor dynein. Both the actr10 mutation and pharmacological dynein inhibition in zebrafish result in failure to properly distribute mbp mRNA in oligodendrocytes, indicating a paradoxical role for the retrograde dynein/dynactin complex in anterograde mbp mRNA transport. To address the molecular mechanism underlying this observation, we biochemically isolated reporter-tagged Mbp mRNA granules from primary cultured mammalian oligodendrocytes to show that they indeed associate with the retrograde motor complex. Next, we used live-cell imaging to show that acute pharmacological dynein inhibition quickly arrests Mbp mRNA transport in both directions. Chronic pharmacological dynein inhibition also abrogates Mbp mRNA distribution and dramatically decreases MBP protein levels. Thus, these cell culture and whole animal studies demonstrate a role for the retrograde dynein/dynactin motor complex in anterograde mbp mRNA transport and myelination in vivo.

reviews

  • https://pubmed.ncbi.nlm.nih.gov/39086020/

    J Neurochem. 2024 Sep;168(9):2227-2242.

    Authors: Bergstrom JJD, Fu MM.

    Abstract:
    Schizophrenic individuals display disrupted myelination patterns, altered oligodendrocyte distribution, and abnormal oligodendrocyte morphology. Schizophrenia is linked with dysregulation of a variety of genes involved in oligodendrocyte function and myelin production. Single-nucleotide polymorphisms (SNPs) and rare mutations in myelination-related genes are observed in certain schizophrenic populations, representing potential genetic risk factors. Downregulation of myelination-related RNAs and proteins, particularly in frontal and limbic regions, is consistently associated with the disorder across multiple studies. These findings support the notion that disruptions in myelination may contribute to the cognitive and behavioral impairments experienced in schizophrenia, although further evidence of causation is needed.

  • https://pubmed.ncbi.nlm.nih.gov/36003149/

    Front Cell Dev Biol. 2022 Aug 8;10:902261.

    Authors: Nowacki JC, Fields AM, Fu MM.

    Abstract:
    Leukodystrophies are a broad spectrum of neurological disorders characterized primarily by deficiencies in myelin formation. Clinical manifestations usually appear during childhood and common symptoms include lack of motor coordination, difficulty with or loss of ambulation, issues with vision and/or hearing, cognitive decline, regression in speech skills, and even seizures. Many cases can be attributed to genetic mutations, but they have diverse inheritance patterns (e.g., autosomal recessive, autosomal dominant, or X-linked) and some arise from de novo mutations. This review provides an updated overview of 35 types of leukodystrophies and focuses on cellular mechanisms that may underlie these disorders. We find common themes in specialized functions in oligodendrocytes, including myelin protein defects, lipid processing and peroxisome dysfunction, transcriptional and translational dysregulation, disruptions in cytoskeletal organization, and cell junction defects. Additionally, non-cell-autonomous factors in astrocytes and microglia, such as autoimmune reactivity and intercellular communication, may also play a role in leukodystrophy onset. Highlighting these themes in cellular dysfunction may yield conceptual insights on future therapeutic approaches.

  • https://pubmed.ncbi.nlm.nih.gov/35964523/

    Curr Opin Cell Biol. 2022 Oct;78:102119.

    Authors: Kemal S, Richardson HS, Dyne ED, Fu MM.

    Abstract:
    Both neurons and glia in mammalian brains are highly ramified. Neurons form complex neural networks using axons and dendrites. Axons are long with few branches and form pre-synaptic boutons that connect to target neurons and effector tissues. Dendrites are shorter, highly branched, and form post-synaptic boutons. Astrocyte processes contact synapses and blood vessels to regulate neuronal activity and blood flow, respectively. Oligodendrocyte processes extend toward axons to make myelin sheaths. Microglia processes dynamically survey their environments. This review describes the local secretory system (ER and Golgi) in neuronal and glial processes, focusing on Golgi outpost functions in acentrosomal microtubule nucleation, cargo trafficking, and protein glycosylation. Satellite ER and Golgi are critical for local structure and function in neurons and glia.

  • https://pubmed.ncbi.nlm.nih.gov/33840591/

    Trends Cell Biol. 2021 Jun;31(6):419-423.

    Authors: Meservey LM, Topkar VV, Fu MM

    Abstract:
    Though mRNA transport and local translation are extensively studied in neurons, emerging evidence supports that these cellular processes are also abundant in non-neuronal glial cells. Here, we explore mechanisms of mRNA transport and local translation in oligodendrocytes, astrocytes, microglia, radial glia, and their functions in development, structure, and intercellular interactions.

  • https://pubmed.ncbi.nlm.nih.gov/32324338/

    Dev Neurobiol. 2021 Apr;81(3):310-320.

    Authors: Weigel M, Wang L, Fu MM.

    Abstract:
    Though much is known about microtubule organization and microtubule-based transport in neurons, the development and function of microtubules in glia are more enigmatic. This review provides an overview of the literature on microtubules in ramified brain cells, including oligodendrocytes, astrocytes, and microglia, focusing on normal cell biology—how structure relates to function in these cells. In oligodendrocytes, microtubules are important for the extension of processes that contact axons and for elongating the myelin sheath. Recent studies demonstrate that new microtubules can form outside of the oligodendrocyte cell body off of Golgi outpost organelles. In astrocytes and microglia, changes in cell shape and ramification can be influenced by neighboring cells and the extracellular milieu. Finally, key papers implicating glial microtubule defects in neurological injury and disease are highlighted, discussing how microtubules may contribute to invasiveness in gliomas. Thus, future research on the mechanisms underlying microtubule organization in normal glial cell function may yield valuable insights into neurological disease pathology.

  • https://pubmed.ncbi.nlm.nih.gov/32863092/

    Trends Cell Biol. 2020 Oct;30(10):792-804.

    Authors: Valenzuela A, Meservey L, Nguyen H, Fu MM.

    Abstract:
    Classically, animal cells nucleate or form new microtubules off the perinuclear centrosome. In recent years, the Golgi outpost has emerged as a satellite organelle that can function as an acentrosomal microtubule-organizing center (MTOC), nucleating new microtubules at distances far from the nucleus or cell body. Golgi outposts can nucleate new microtubules in specialized cells with unique cytoarchitectures, including Drosophila neurons, mouse muscle cells, and rodent oligodendrocytes. This review compares and contrasts topics of functional relevance, including Golgi outpost heterogeneity, formation and transport, as well as regulation of microtubule polarity and branching. Golgi outposts have also been implicated in the pathology of diseases, including muscular dystrophy and neurodegenerative diseases such as Parkinson's disease. Since Golgi outposts are relatively understudied, many outstanding questions regarding their function and roles in disease remain.