About

H. Robert Horvitz is the David H. Koch Professor at MIT, a member of the McGovern Institute for Brain Research, and a member of the David H.. Koch Institute for Integrative Cancer Research. He is also an Investigator at the Howard Hughes Medical Institute. His research focuses on analyzing the roles of genes in animal development and behavior, using the nematode Caenorhabditis elegans as an experimental model. His work aims to identify and analyze molecular and cellular pathways involved in these biological processes, with the ultimate goal of clarifying fundamental mechanisms and providing insights into human disease.

Research topics

• Biology
• Cell biology
• Genetics
• Neuroscience
• Molecular biology

Selected publications

• Author Reply to Peer Reviews of Programmed Cell Death Modifies Neural Circuits and Tunes Intrinsic Behavior

  2026-04-19

  peer-review
  PublisherDOI

• From nematode to Nobel: How community-shared resources fueled the rise of <i>Caenorhabditis elegans</i> as a research organism

  Proceedings of the National Academy of Sciences · 2025-11-24 · 3 citations

  articleOpen access

  Experimental organisms such as the nematode Caenorhabditis elegans are fundamental to biological discovery. The success of C. elegans research has been greatly enabled by infrastructure that allows thousands of scientists to share and access research materials and unpublished information efficiently. Here, we celebrate the worm by interweaving vignettes describing four Nobel Prize–winning discoveries with descriptions of how the major NIH-supported research resources—the Caenorhabditis Genetics Center, WormBase, and WormAtlas—provide invaluable support for all C. elegans research. The synergy between investigation and the availability of shared resources for the C. elegans community is a paradigm for all model organism research, and the continued support of such community research resources will be essential for maximizing impactful discoveries in the future.

  PublisherOA PDFDOI

• Transcriptional landscape of a hypoxia response identifies cell-specific pathways for adaptation

  bioRxiv (Cold Spring Harbor Laboratory) · 2024-07-04

  preprintOpen accessSenior authorCorresponding

  Abstract How the HIF-1 (Hypoxia-Inducible) transcription factor drives and coordinates distinct responses to low oxygen across diverse cell types is poorly understood. We present a multi-tissue single-cell gene-expression atlas of the hypoxia response of the nematode Caenorhabditis elegans . This atlas highlights how cell-type-specific HIF-1 responses overlap and diverge among and within neuronal, intestinal, and muscle tissues. Using the atlas to guide functional analyses of candidate muscle-specific HIF-1 effectors, we discovered that HIF-1 activation drives downregulation of the tspo-1 ( TSPO, Translocator Protein) gene in vulval muscle cells to modulate a hypoxia-driven change in locomotion caused by contraction of body-wall muscle cells. We further showed that in human cardiomyocytes HIF-1 activation decreases levels of TSPO and thereby alters intracellular cholesterol transport and the mitochondrial network. We suggest that TSPO-1 is an evolutionarily conserved mediator of HIF-1-dependent modulation of muscle and conclude that our gene-expression atlas can help reveal how HIF-1 drives cell-specific adaptations to hypoxia.

  PublisherOA PDFDOI

• Deletion of VPS50 protein in mouse brain impairs synaptic function and behavior

  BMC Biology · 2024-06-26 · 2 citations

  articleOpen access

  BACKGROUND: The VPS50 protein functions in synaptic and dense core vesicle acidification, and perturbations of VPS50 function produce behavioral changes in Caenorhabditis elegans. Patients with mutations in VPS50 show severe developmental delay and intellectual disability, characteristics that have been associated with autism spectrum disorders (ASDs). The mechanisms that link VPS50 mutations to ASD are unknown. RESULTS: To examine the role of VPS50 in mammalian brain function and behavior, we used the CRISPR/Cas9 system to generate knockouts of VPS50 in both cultured murine cortical neurons and living mice. In cultured neurons, KO of VPS50 did not affect the number of synaptic vesicles but did cause mislocalization of the V-ATPase V1 domain pump and impaired synaptic activity, likely as a consequence of defects in vesicle acidification and vesicle content. In mice, mosaic KO of VPS50 in the hippocampus altered synaptic transmission and plasticity and generated robust cognitive impairments. CONCLUSIONS: We propose that VPS50 functions as an accessory protein to aid the recruitment of the V-ATPase V1 domain to synaptic vesicles and in that way plays a crucial role in controlling synaptic vesicle acidification. Understanding the mechanisms controlling behaviors and synaptic function in ASD-associated mutations is pivotal for the development of targeted interventions, which may open new avenues for therapeutic strategies aimed at ASD and related conditions.

  PublisherOA PDFDOI

• The pro-apoptotic function of the <i>C. elegans</i> BCL-2 homolog CED-9 requires interaction with the APAF-1 homolog CED-4

  Science Advances · 2024-10-09 · 6 citations

  articleOpen accessSenior authorCorresponding

  In Caenorhabditis elegans , apoptosis is inhibited by the BCL-2 homolog CED-9. Although canonically anti-apoptotic, CED-9 has a poorly understood pro-apoptotic function. CED-9 is thought to inhibit apoptosis by binding to and inhibiting the pro-apoptotic C. elegans APAF-1 homolog CED-4. We show that CED-9 or CED-4 mutations located in their CED-9–CED-4 binding regions reduce apoptosis without affecting the CED-9 anti-apoptotic function. These mutant CED-9 and CED-4 proteins are defective in a CED-9–CED-4 interaction in vitro and in vivo, revealing that the known CED-9–CED-4 interaction is required for the pro-apoptotic but not for the anti-apoptotic function of CED-9. The pro-apoptotic CED-9–CED-4 interaction occurs at mitochondria. In mammals, BCL-2 family members can activate APAF-1 via cytochrome c release from mitochondria. The conserved role of mitochondria in CED-9/BCL-2–dependent CED-4/APAF-1 activation is notable and suggests that understanding how CED-9 promotes apoptosis in C. elegans could inform the understanding of mammalian apoptosis and how disruptions of apoptosis promote certain human disorders.

  PublisherDOI

• Deletion of VPS50 protein in mice brain impairs synaptic function and behavior

  bioRxiv (Cold Spring Harbor Laboratory) · 2023-07-05

  preprintOpen access

  VPS50, is an accessory protein, involved in the synaptic and dense core vesicle acidification and its alterations produce behavioral changes in C.elegans. Here, we produce the mosaic knock out (mKO) of VPS50 using CRISPR/Cas9 system in both cortical cultured neurons and whole animals to evaluate the effect of VPS50 in regulating mammalian brain function and behavior. While mKO of VPS50 does not change the number of synaptic vesicles, it produces a mislocalization of the V-ATPase pump that likely impact in vesicle acidification and vesicle content to impair synaptic and neuronal activity in cultured neurons. In mice, mKO of VPS50 in the hippocampus, alter synaptic transmission and plasticity, and generated robust cognitive impairments associate to memory formation. We propose that VPS50 is an accessory protein that aids the correct recruitment of the V-ATPase pump to synaptic vesicles, thus having a crucial role controlling synaptic vesicle acidification and hence synaptic transmission.

  PublisherOA PDFDOI

• A DEAD-box helicase drives the partitioning of a pro-differentiation NAB protein into nuclear foci

  Nature Communications · 2023-10-18 · 3 citations

  articleOpen accessSenior author

  How cells regulate gene expression in a precise spatiotemporal manner during organismal development is a fundamental question in biology. Although the role of transcriptional condensates in gene regulation has been established, little is known about the function and regulation of these molecular assemblies in the context of animal development and physiology. Here we show that the evolutionarily conserved DEAD-box helicase DDX-23 controls cell fate in Caenorhabditis elegans by binding to and facilitating the condensation of MAB-10, the C. elegans homolog of mammalian NGFI-A-binding (NAB) protein. MAB-10 is a transcriptional cofactor that functions with the early growth response (EGR) protein LIN-29 to regulate the transcription of genes required for exiting the cell cycle, terminal differentiation, and the larval-to-adult transition. We suggest that DEAD-box helicase proteins function more generally during animal development to control the condensation of NAB proteins important in cell identity and that this mechanism is evolutionarily conserved. In mammals, such a mechanism might underlie terminal cell differentiation and when dysregulated might promote cancerous growth.

  PublisherOA PDFDOI

• Programmed Cell Death Modifies Neural Circuits and Tunes Intrinsic Behavior

  bioRxiv (Cold Spring Harbor Laboratory) · 2023-09-14 · 3 citations

  preprintOpen access

  Summary Programmed cell death (PCD) is a common feature of animal development. During development of the C. elegans hermaphrodite, programmed cell death eliminates 131 cells in stereotyped positions in the cell lineage, mostly in neuronal lineages. Blocking cell death results in supernumerary “undead” neurons. We find that undead neurons can be wired into circuits, can display activity, and can modify specific behaviors. The two undead RIM-like neurons participate in the RIM-containing circuit that computes movement. The presence of these two extra neurons results in animals that initiate fewer reversals and lengthens the duration of those reversals that do occur. We describe additional behavioral alterations of cell-death mutants, including in locomotory turning angle and pharyngeal pumping. These findings indicate that physiological or evolutionary variations in PCD might reveal latent neuronal elements that the nervous system can incorporate to modify nervous system function and animal behavior.

  PublisherOA PDFDOI

• The transcriptional corepressor CTBP-1 acts with the SOX family transcription factor EGL-13 to maintain AIA interneuron cell identity in Caenorhabditis elegans

  DSpace@MIT (Massachusetts Institute of Technology) · 2022-01-01 · 4 citations

  articleOpen accessSenior author

  Cell identity is characterized by a distinct combination of gene expression, cell morphology, and cellular function established as progenitor cells divide and differentiate. Following establishment, cell identities can be unstable and require active and continuous maintenance throughout the remaining life of a cell. Mechanisms underlying the maintenance of cell identities are incompletely understood. Here, we show that the gene ctbp-1, which encodes the transcriptional corepressor C-t erminal b inding p rotein-1 (CTBP-1), is essential for the maintenance of the identities of the two AIA interneurons in the nematode Caenorhabditis elegans. ctbp-1 is not required for the establishment of the AIA cell fate but rather functions cell-autonomously and can act in later larval stage and adult worms to maintain proper AIA gene expression, morphology and function. From a screen for suppressors of the ctbp-1 mutant phenotype, we identified the gene egl-13, which encodes a SOX family transcription factor. We found that egl-13 regulates AIA function and aspects of AIA gene expression, but not AIA morphology. We conclude that the CTBP-1 protein maintains AIA cell identity in part by utilizing EGL-13 to repress transcriptional activity in the AIAs. More generally, we propose that transcriptional corepressors like CTBP-1 might be critical factors in the maintenance of cell identities, harnessing the DNA-binding specificity of transcription factors like EGL-13 to selectively regulate gene expression in a cell-specific manner.

  Publisher

• A DEAD-box helicase drives the partitioning of a pro-differentiation NAB protein into nuclear foci

  bioRxiv (Cold Spring Harbor Laboratory) · 2022-03-29

  preprintOpen accessSenior authorCorresponding

  Abstract How cells regulate gene expression in a precise spatiotemporal manner during organismal development is a fundamental question in biology. Recent studies have demonstrated the role of transcriptional condensates in gene regulation 1–5 . However, little is known about the function and regulation of these transcriptional condensates in the context of animal development and physiology. We found that the evolutionarily conserved DEAD-box helicase DDX-23 controls stem cell fate in C. elegans at least in part by binding to and facilitating the condensation of MAB-10, the C. elegans homolog of mammalian NAB protein. MAB-10 is a transcriptional cofactor that functions with the EGR protein LIN-29 to regulate the transcription of genes required for exiting the cell cycle, terminal differentiation, and the larval-to-adult transition 6 . We suggest that DEAD-box helicase proteins function more generally during animal development to control the condensation of NAB proteins important in cell-fate decisions and that this mechanism is evolutionarily conserved. In mammals, a comparable mechanism might underlie terminal cell differentiation and when misregulated might promote cancerous growth.

  PublisherOA PDFDOI

Recent grants

• NIH Grant R37GM024663

  NIH · $3.2M · 2000

• NIH Grant K04HD000369

  NIH · $58k · 1986

• Genetic Analysis of Nematode Egg Laying and Co-regulated Behavioral Systems

  NIH · $11.4M · 1978–2027

• NIH Grant R01GM024943

  NIH · $747k · 1991

• NIH Grant R03HD075076

  NIH · $154k · 2015

Frequent coauthors

• Peter C. Sapp

  University of Massachusetts Chan Medical School

  118 shared

• Robert H. Brown

  University of Massachusetts Chan Medical School

  114 shared

• Ezequiel Alvarez-Saavedra

  109 shared

• Eric A. Miska

  University of Cambridge

  107 shared

• Nikhil Bhatla

  University of California, Berkeley

  67 shared

• Eugène Berezikov

  University of Groningen

  64 shared

• Erno Wienholds

  Ontario Genomics

  64 shared

• Wigard P. Kloosterman

  64 shared

Labs

• H. Robert Horvitz LabPI

Education

• Ph.D., Biology

  Harvard University

  1974

• M.A., Biology

  Harvard University

  1972

• S.B., Economics

  Massachusetts Institute of Technology

  1968

• S.B., Mathematics

  Massachusetts Institute of Technology

  1968

Awards & honors

• U.S. National Academy of Inventors, Member, 2015
• American Association for Cancer Research Academy, Fellow, 20…
• Royal Society of London, Foreign Member, 2009
• Genetics Society (U.K.), Mendel Medal, 2007
• Eli Lilly Lecturer Award, 2007