About

Professor Andrew Chisholm is associated with the MRC Laboratory of Molecular Biology (LMB), a research institute dedicated to understanding fundamental biological processes at the levels of atoms, molecules, cells, and organisms. The LMB has pioneered the molecular biology revolution since its origins in 1947 and is recognized as a world-leading source of new ideas, scientific advances, and technology. The institute's research spans a broad spectrum of biology, supported by cutting-edge facilities and core funding from the MRC/UKRI. While the specific research focus of Professor Chisholm is not detailed in the provided page text, the institute's overarching mission involves discovering how life works through scientific research that has led to successful commercializations and medical advances. The LMB's environment fosters ambitious research across over 50 scientific groups, contributing to advances in understanding complex biological systems, such as neural connections, DNA replication machinery, and cellular signaling networks. The institute also emphasizes public engagement and inspiring future generations of scientists.

Research topics

• Biology
• Cell biology
• Psychology
• Genetics
• Neuroscience
• Evolutionary biology
• Composite material
• Anatomy
• Internal medicine
• Materials science
• Biophysics
• Biochemistry
• Chemistry

Selected publications

• A defining member of the new cysteine-cradle family is an aECM protein signalling skin damage in C. elegans

  PLoS Genetics · 2025-03-20 · 4 citations

  articleOpen access

  Apical extracellular matrices (aECMs) act as crucial barriers, and communicate with the epidermis to trigger protective responses following injury or infection. In Caenorhabditis elegans, the skin aECM, the cuticle, is produced by the epidermis and is decorated with periodic circumferential furrows. We previously showed that mutants lacking cuticle furrows exhibit persistent immune activation (PIA), providing a valuable model to study the link between cuticle damage and immune response. In a genetic suppressor screen, we identified spia-1 as a key gene downstream of furrow collagens and upstream of immune signalling. spia-1 expression oscillates during larval development, peaking between each moult together with patterning cuticular components. It encodes a secreted protein that localises to furrows. SPIA-1 shares a novel cysteine-cradle domain with other aECM proteins. SPIA-1 mediates immune activation in response to furrow loss and is proposed to act as an extracellular signal activator of cuticle damage. This research provides a molecular insight into intricate interplay between cuticle integrity and epidermal immune activation in C. elegans.

  PublisherOA PDFDOI

• Phospholipid biogenesis maintains neuronal integrity during aging and axon regeneration

  Genetics · 2025-06-25 · 1 citations

  articleOpen accessSenior author

  Neurons maintain their morphology over prolonged periods of adult life with limited regenerative capacity. Among the various factors that shape neuronal morphology, lipids function as membrane components, signaling molecules, and regulators of synaptic plasticity. Here, we tested genes involved in phospholipid biosynthesis and identified their roles in axon regrowth and maintenance. CEPT-2 and EPT-1 are enzymes catalyzing the final steps in the de novo phospholipid synthesis (Kennedy) pathway. Loss of function mutants of cept-2 or ept-1 show reduced axon regrowth and failure to maintain axon morphology. We demonstrate that CEPT-2 is required cell-autonomously to prevent age-related axonal morphology defects. We further investigated genetic interactions of cept-2 or ept-1 with dip-2, a conserved regulator of lipid metabolism that affects axon morphology maintenance and regrowth after injury. Loss-of-function in dip-2 led to suppression of axon regrowth defects observed in either cept-2 or ept-2 mutants, suggesting that DIP-2 acts to counterbalance phospholipid synthesis. Our findings reveal the genetic regulation of lipid metabolism as critical for axon maintenance following injury and during aging.

  PublisherOA PDFDOI

• Multiscale patterning of a model apical extracellular matrix revealed by systematic endogenous protein tagging

  bioRxiv (Cold Spring Harbor Laboratory) · 2025-05-14 · 9 citations

  preprintOpen access

  Abstract Barrier epithelia are shielded from the external environment by their apical extracellular matrices (aECMs). The molecular complexity of aECMs has challenged understanding of their organization in vivo . To define the molecular architecture of a model aECM we generated a toolkit of 102 fluorescently tagged aECM components using gene editing in C. elegans , focusing on proteins secreted by the epidermis to form the collagen-rich cuticle. We developed efficient pipelines for modular protein tagging and rapid fluorophore swapping. Most tagged collagens were functional and exhibited exquisitely specific patterning across stages, cell types, and matrix substructures. We define multiple reference markers for key substructures including the little-understood cortical layer, as well as the helical crossed fiber arrays that function as a hydrostatic skeleton to maintain organismal shape. We further tagged >30 members of key aECM protein classes including proteases, protease inhibitors, and lipid transporters. Our standardized markers will allow dissection of the mechanistic basis of aECM spatiotemporal patterning in vivo . Highlights First large-scale protein tagging resource for the apical extracellular matrix Optimization of CRISPR methods for protein tagging including color swaps Tagged proteins are functional and exhibit a high degree of stage-, cell- and compartment specificity Reference localization patterns for multiple aECM compartments and markers for newly defined compartments

  PublisherOA PDFDOI

• Context-specific interaction of the lipid regulator DIP-2 with phospholipid synthesis in axon regeneration and maintenance

  bioRxiv (Cold Spring Harbor Laboratory) · 2025-02-08

  preprintOpen accessSenior authorCorresponding

  Abstract Neurons maintain their morphology over prolonged periods of adult life with limited regeneration after injury. C. elegans DIP-2 is a conserved regulator of lipid metabolism that affects axon maintenance and regeneration after injury. Here, we investigated genetic interactions of dip-2 with mutants in genes involved in lipid biosynthesis and identified roles of phospholipids in axon regrowth and maintenance. CEPT-2 and EPT-1 are enzymes catalyzing the final steps in the de novo phospholipid synthesis (Kennedy) pathway. Loss of function mutants of cept-2 or ept-1 show reduced axon regrowth and failure to maintain axon morphology. We demonstrate that CEPT-2 is cell-autonomously required to prevent age-related axonal defects. Interestingly, loss of function in dip-2 led to suppression of the axon regrowth phenotype observed in either cept-2 or ept-2 mutants, suggesting that DIP-2 acts to counterbalance phospholipid synthesis. Our findings reveal the genetic regulation of lipid metabolism to be critical for axon maintenance under injury and during aging. Article Summary Little is known about how adult neurons live long with limited regenerative capacity. This study investigates the role of lipid metabolism in sustaining neuronal health in C. elegans. Mutating phospholipid synthetic genes impairs axon regrowth after injury. Lack of DIP-2, a lipid regulator, restores regrowth, suggesting DIP-2 counterbalances phospholipid synthesis. Moreover, neuronal phospholipid synthesis is essential for preventing age-dependent axonal defects. These findings reveal phospholipid biosynthesis is key to axon integrity during aging and injury. As lipid metabolism is implicated in neurological disorders, this study serves as an entry point into investigating neuronal lipid biology under various conditions.

  PublisherOA PDFDOI

• <i>C. elegans</i> epicuticlins define specific compartments in the apical extracellular matrix and function in wound repair

  bioRxiv (Cold Spring Harbor Laboratory) · 2024-01-13 · 1 citations

  preprintOpen accessSenior authorCorresponding

  Abstract The apical extracellular matrix (aECM) of external epithelia often contains lipid-rich outer layers that contribute to permeability barrier function. The external aECM of nematode is known as the cuticle and contains an external lipid-rich layer, the epicuticle. Epicuticlins are a family of tandem repeat proteins originally identified as components of the insoluble fraction of the cuticular aECM and thought to localize in or near epicuticle. However, there has been little in vivo analysis of epicuticlins. Here, we report the localization analysis of the three C. elegans epicuticlins (EPIC proteins) using fluorescent protein knock-ins to visualize endogenously expressed proteins, and further examine their in vivo function using genetic null mutants. By TIRF microscopy, we find that EPIC-1 and EPIC-2 localize to the surface of the cuticle in larval and adult stages in close proximity to the outer lipid layer. EPIC-1 and EPIC-2 also localize to interfacial cuticles and adult-specific cuticle struts. EPIC-3 expression is restricted to the stress-induced dauer stage, where it localizes to interfacial aECM in the buccal cavity. Strikingly, skin wounding in the adult induces epic-3 expression, and EPIC-3::mNG localizes to wound scars. Null mutants lacking one, two, or all three EPIC proteins display reduced survival after skin wounding yet are viable with low penetrance defects in epidermal morphogenesis. Our results suggest EPIC proteins define specific aECM compartments and have roles in wound repair. Highlights C. elegans epicuticlin (EPIC) proteins localize to specific regions in cortical and interfacial cuticle Epicuticlins colocalize with BLI collagens in struts in adult cuticle EPIC-3 is normally expressed in dauer stage and upregulated by skin wounding Mutants lacking all three epicuticlins are viable and show reduced survival after skin wounding

  PublisherOA PDFDOI

• The BEN domain protein LIN-14 coordinates neuromuscular positioning during epidermal maturation

  iScience · 2024-12-12

  articleOpen access

  mutants show defects in formation of epidermis-muscle attachment complex hemidesmosomes in the maturing ventral epidermis, leading to detachment of muscles and motor neurons as well as movement defects. Our findings reveal a cell non-autonomous role for LIN-14 in coordinating inter-tissue interaction and neuromuscular positioning during epidermal maturation.

  PublisherDOI

• Dopey-dependent regulation of extracellular vesicles maintains neuronal morphology

  bioRxiv (Cold Spring Harbor Laboratory) · 2024-05-08

  preprintOpen accessSenior authorCorresponding

  ABSTRACT Mature neurons maintain their distinctive morphology for extended periods in adult life. Compared to developmental neurite outgrowth, axon guidance, and target selection, relatively little is known of mechanisms that maintain mature neuron morphology. Loss of function in C. elegans DIP-2, a member of the conserved lipid metabolic regulator Dip2 family, results in progressive overgrowth of neurites in adults. We find that dip-2 mutants display specific genetic interactions with sax-2 , the C. elegans ortholog of Drosophila Furry and mammalian FRY. Combined loss of DIP-2 and SAX-2 results in severe disruption of neuronal morphology maintenance accompanied by increased release of neuronal extracellular vesicles (EVs). By screening for suppressors of dip-2 sax-2 double mutant defects we identified gain-of-function ( gf ) mutations in the conserved Dopey family protein PAD-1 and its associated phospholipid flippase TAT-5/ATP9A. In dip-2 sax-2 double mutants carrying either pad-1(gf) or tat-5(gf) mutation, EV release is reduced and neuronal morphology across multiple neuron types is restored to largely normal. PAD-1(gf) acts cell autonomously in neurons. The domain containing pad-1 ( gf ) is essential for PAD-1 function, and PAD-1( gf ) protein displays increased association with the plasma membrane and inhibits EV release. Our findings uncover a novel functional network of DIP-2, SAX-2, PAD-1, and TAT-5 that maintains morphology of neurons and other types of cells, shedding light on the mechanistic basis of neurological disorders involving human orthologs of these genes.

  PublisherOA PDFDOI

• The microtubule regulator EFA-6 forms spatially restricted cortical foci dependent on its intrinsically disordered region and interactions with tubulins

  bioRxiv (Cold Spring Harbor Laboratory) · 2024-04-14

  preprintOpen accessSenior authorCorresponding

  ABSTRACT Microtubules (MTs) are dynamic components of the cytoskeleton and play essential roles in morphogenesis and maintenance of tissue and cell integrity. Despite recent advances in understanding MT ultrastructure, organization, and growth control, how cells regulate MT organization at the cell cortex remains poorly understood. The EFA-6/EFA6 proteins are recently identified membrane-associated proteins that inhibit cortical MT dynamics. Here, combining visualization of endogenously tagged C. elegans EFA-6 with genetic screening, we uncovered tubulin-dependent regulation of EFA-6 patterning. In the mature epidermal epithelium, EFA-6 forms punctate foci in specific regions of the apical cortex, dependent on its intrinsically disordered region (IDR). We further show the EFA-6 IDR is sufficient to form biomolecular condensates in vitro . In screens for mutants with altered GFP::EFA-6 localization, we identified a novel gain-of-function (gf) mutation in an α-tubulin tba-1 that induces ectopic EFA-6 foci in multiple cell types. tba-1(gf) animals exhibit temperature-sensitive embryonic lethality, which is partially suppressed by efa-6(lf) , indicating the interaction between tubulins and EFA-6 is important for normal development. TBA-1(gf) shows reduced incorporation into filamentous MTs but has otherwise mild effects on cellular MT organization. The ability of TBA-1(gf) to trigger ectopic EFA-6 foci formation requires β-tubulin TBB-2 and the chaperon EVL-20/Arl2. The tba-1(gf)- induced EFA-6 foci display slower turnover, contain the MT-associated protein TAC-1/TACC, and require the EFA-6 MTED. Our results reveal a novel crosstalk between cellular tubulins and cortical MT regulators in vivo . Highlights The MT regulator EFA-6 forms spatially restricted punctate cortical foci The EFA-6 N-terminal intrinsically disordered region (IDR) is essential for the formation of cortical foci in vivo and is sufficient for droplet formation in vitro Tubulins regulate formation of EFA-6 foci via the EFA-6 MT elimination domain EFA-6 foci induced by altered tubulin heterodimer function display reduced turnover and recruit TAC-1/TACC

  PublisherOA PDFDOI

• The microtubule regulator EFA-6 forms cortical foci dependent on its intrinsically disordered region and interactions with tubulins

  Cell Reports · 2024-09-20

  articleOpen accessSenior author

  The EFA6 protein family, originally identified as Sec7 guanine nucleotide exchange factors, has also been found to regulate cortical microtubule (MT) dynamics. Here, we find that in the mature C. elegans epidermal epithelium, EFA-6 forms punctate foci in specific regions of the apical cortex, dependent on its intrinsically disordered region (IDR). The EFA-6 IDR can form biomolecular condensates in vitro. In genetic screens for mutants with altered GFP::EFA-6 localization, we identified a gain-of-function (gf) mutation in α-tubulin tba-1 that induces ectopic EFA-6 foci in multiple cell types. Lethality of tba-1(gf) is partially suppressed by loss of function in efa-6. The ability of TBA-1(gf) to trigger ectopic EFA-6 foci requires β-tubulin TBB-2 and the chaperon EVL-20/Arl2. tba-1(gf)-induced EFA-6 foci display slower turnover, contain the MT-associated protein TAC-1/TACC, and require the EFA-6 MT elimination domain (MTED). Our results reveal functionally important crosstalk between cellular tubulins and cortical MT regulators in vivo.

  PublisherDOI

• Dopey-dependent regulation of extracellular vesicles maintains neuronal morphology

  Current Biology · 2024-10-07 · 5 citations

  articleOpen accessSenior author
  PublisherOA PDFDOI

Recent grants

• US-France Cooperative Research: Cell Adhesion and Innate Immunity in C. Elegans

  NSF · $3k · 2007–2008

• Maintenance and Repair of the C. elegans Skin

  NIH · $2.1M · 2019–2024

• Cellular Dynamics of Axon Regeneration

  NIH · $3.7M · 2015–2024

• NIH Grant R56NS057317

  NIH · $388k · 2016

• Mechanisms of Tissue Morphogenesis in C. elegans

  NIH · $6.4M · 1997–2020

Frequent coauthors

• Yishi Jin

  University of California, San Diego

  72 shared

• Melbourne Bryant

  Virginia Department of Game and Inland Fisheries

  25 shared

• St D'arton

  State Street (United States)

  25 shared

• Tuerong

  State Street (United States)

  25 shared

• John G. Barrett

  25 shared

• H Forp

  Yarra Valley Water (Australia)

  25 shared

• Mel- Bourne Gibson-Carmichael

  State Street (United States)

  25 shared

• Gary C. Dennis

  25 shared

Awards & honors

• Lucille P Markey postdoctoral fellowship