About

Daniel Lew is a professor of biology at MIT who uses fungal model systems to investigate how cells orient their activities in space. His research focuses on understanding how different cell shapes arise and how cells control the spatial distribution of their internal constituents, which is critical for performing specialized functions such as nutrient absorption and muscle contraction. Lew employs approaches from cell biology, genetics, and computational biology to elucidate molecular mechanisms underlying these processes. His work contributes to a deeper understanding of cell orientation, polarization, and organelle segregation, with implications for cell function and development.

Research topics

• Biology
• Cell biology
• Genetics
• Biophysics
• Chemistry

Selected publications

• Septins and cytokinesis in the polymorphic fungus <i>Aureobasidium pullulans</i>

  bioRxiv (Cold Spring Harbor Laboratory) · 2026-01-21

  articleSenior author

  ABSTRACT During cytokinesis of animals and fungi, a contractile actomyosin ring (CAR) assembles at target locations and constricts to drive cell separation. In animal cells, the position of the CAR is determined by the mitotic spindle, so that the cleavage plane is perpendicular to the mitotic axis. However, in budding yeasts, the location of CAR assembly is specified by a cortical septin cytoskeleton that recruits CAR components to the neck. In the polymorphic fungus Aureobasidium pullulans , we show that septins assemble at mother-bud necks and predict the site of CAR assembly. Cells lacking septins stochastically failed to assemble CARs at a subset of bud necks. However, even cells lacking all four core septins were able to assemble CARs at 75% of bud necks. Our findings suggest the existence of a novel CAR positioning strategy that requires neither septin scaffolds nor nuclear/spindle cues to enable CAR assembly and constriction at bud necks. eTOC SUMMARY Budding yeasts are thought to use septins to mark mother-bud necks as sites for cytokinesis. Here, we find that the multibudding yeast Aureobasidium pullulans can position cytokinetic machinery at most bud necks even in the absence of septins, revealing a novel pathway to mark cytokinesis sites.

  PublisherDOI

• Organelle scaling over a 100-fold cell size range

  bioRxiv (Cold Spring Harbor Laboratory) · 2026-05-13

  articleOpen accessSenior authorCorresponding

  ABSTRACT Cell size in a proliferating cell population generally varies over a limited range (∼2-4-fold). Within such populations, organelle content increases with cell size maintaining a relatively constant organelle density (amount per cell volume). However, cells of different types can differ greatly in cell size as well as in organelle composition. In such cases, it is often unclear to what degree, if any, the differences in organelle composition are due to the difference in cell size. In principle, this issue could be resolved by examining situations where a proliferating population of cells of the same cell type exhibit much greater size variation. Here we characterize how organelle content scales with cell volume in the polymorphic fungus, A. pullulans , whose proliferating cells span a ∼100-fold size range. We find that mitochondria and ER content increases in proportion to cell volume, while this is not the case for vacuoles and peroxisomes. Thus, organelle composition is affected by cell size in this system.

  PublisherDOI

• Organelle partitioning in the multi-budding yeast <i>Aureobasidium pullulans</i>

  bioRxiv (Cold Spring Harbor Laboratory) · 2026-04-21 · 1 citations

  articleOpen accessSenior authorCorresponding

  Cellular organelle content is fairly constant within a given cell type. This is accomplished in part by ensuring equitable organelle partitioning during division. Much of our understanding of organelle inheritance has come from investigating cells that divide in half producing two daughter cells. However, more elaborate division strategies that give rise to multiple daughters are not uncommon in nature. Here, we present the first characterization of organelle inheritance in a fungus that grows by multi-budding, producing several (2-20) daughter cells in a single cell cycle. We find that some organelles (mitochondria and ER) are evenly delivered to all growing buds, while others (vacuole and peroxisomes) are more variably inherited. We discuss the implications of even and uneven inheritance for this polyextremotolerant fungus capable of growing in dynamic, and diverse, environments.

  PublisherOA PDFDOI

• Optimized vectors for genetic engineering of <i>Aureobasidium pullulans</i>

  bioRxiv (Cold Spring Harbor Laboratory) · 2025-01-27 · 4 citations

  preprintOpen accessSenior authorCorresponding

  ABSTRACT Aureobasidium pullulans is a polyextremotolerant black yeast that exhibits impressive morphological plasticity. Consequently, it shows promise as a model system for investigating mechanisms of cell adaptation to different environments and the regulation of cell shape. Here, we build upon the current toolkit for working with A. pullulans and design and test 25 vectors with seven different codon-optimized fluorophores and three selection cassettes. This includes vectors that allow for dual expression of GFP and mCherry tagged proteins at the URA3 locus and vectors that enable homology-based deletion or C-terminal tagging of endogenous genes without the need for cloning. This versatile vector series for working with A. pullulans will enable a broad range of experiments in this emerging model system. SUMMARY An optimized plasmid toolkit for genetic engineering of the emerging model fungus, A. pullulans .

  PublisherOA PDFDOI

• Mechanisms of nuclear segregation in a multinucleate multibudding yeast

  The Journal of Cell Biology · 2025-08-12 · 4 citations

  articleOpen accessSenior author

  Budding yeasts present an especially challenging geometry for segregation of chromosomes, which must be delivered across the narrow mother-bud neck into the bud. Studies in the model yeast Saccharomyces cerevisiae have revealed an elaborate set of mechanisms that selectively orient one mitotic spindle pole toward the bud and then drive spindle elongation along the mother-bud axis, ensuring nuclear segregation between mother and bud. It is unclear how these pathways might be adapted to yield similar precision in more complex cell geometries. Here, we provide the first description of the dynamics of mitosis in a multinucleate, multibudding yeast, Aureobasidium pullulans, and identify many unexpected differences from uninucleate yeasts. Mitotic spindles do not orient along the mother-bud axis prior to anaphase, and accurate nuclear segregation often occurs after spindle disassembly. Cortical Num1-dynein forces pull highly mobile nuclei into buds, and once a nucleus enters a bud, it discourages others from entering, ensuring that most daughters inherit only one nucleus.

  PublisherOA PDFDOI

• Ratiometric signaling produces robust temporal integration for accurate cellular gradient sensing

  bioRxiv (Cold Spring Harbor Laboratory) · 2025-04-24 · 2 citations

  preprintOpen accessSenior authorCorresponding

  Cells excel at interpreting noisy chemical gradients to guide fertilization, development, and immune responses, but the mechanisms underlying this remarkable ability remain poorly understood. Previous work showed that some G protein signaling pathways can overcome challenges from uneven receptor distribution by using a ratiometric signaling strategy. In this mechanism, G proteins receive information from both bound and unbound receptors, unlike classical signaling where only bound receptors contribute. Here, we show that ratiometric signaling also provides an unexpected ability to suppress noise from low receptor numbers. The benefit stems from each G protein remembering the last receptor state it encountered, so that at any instant, ratiometric G protein collectives reflect time-averaged receptor activity. Unlike classical signaling, this averaging remains unbiased and accurate across the varying ligand concentrations present in a spatial gradient. Using theory and simulations, we demonstrate that this averaging mechanism allows cells to surpass theoretical limits for gradient detection from instantaneous receptor information alone. Our findings reveal how ratiometric biochemical architectures enable robust temporal integration across spatially varying signals, providing cells with enhanced directional accuracy under noisy conditions.

  PublisherOA PDFDOI

• Regulation of the Cell Wall Integrity pathway at the contact site between mating partners in yeast

  The Journal of Cell Biology · 2025-08-13 · 1 citations

  preprintOpen accessCorresponding

  ABSTRACT The fungal cell wall is constantly remodeled to allow cell growth, but any holes in the cell wall would lead to catastrophic lysis. The “Cell Wall Integrity” pathway (CWI) detects cell wall defects and promotes cell wall thickening or repair to protect cell integrity. However, cell walls must be removed at contact sites between fusing cells during mating or mycelium formation. Here we show that in Saccharomyces cerevisiae , the CWI is downregulated specifically at the contact site between mating cells. A key component of the CWI, Pkc1, accumulated at polarity sites (shmoo tips) in cells exposed to mating pheromone, but not at contact sites. Pkc1 exclusion required a cell wall protein, Fig2, induced by pheromone. In mutants lacking Fig2, cell wall removal was delayed, blocked, or even reversed after transient fusion, leading to reduced mating. These results suggest that Fig2 designates the contact site as a “safe” spot to degrade the cell wall. eTOC Curtis and Lew show that the fungal “Cell Wall Integrity” repair pathway is silenced at contact sites between mating partners to allow cell wall degradation and fusion. They identify a cell wall protein needed to distinguish the contact site as a safe spot for wall removal.

  PublisherOA PDFDOI

• Negative Feedback Equalizes Polarity Sites in a Multi-Budding Yeast

  SSRN Electronic Journal · 2025-01-01

  preprintOpen access
  PublisherDOI

• Negative feedback equalizes polarity sites in a multi-budding yeast

  Current Biology · 2025-11-01

  articleOpen access
  PublisherOA PDFDOI

• Allocation of resources among multiple daughter cells

  The Journal of Cell Biology · 2025-08-05 · 3 citations

  articleSenior author

  Cell division commonly produces two daughter cells, but there are many exceptions where large cells produce multiple daughters. Multiple fission of some green algae and bacteria; cellularization during embryogenesis of plants and insects; and growth of Ichthyosporeans, Chytrids, and Apicomplexans all provide variations on this theme. In some yeast species, a large multinucleate mother cell grows multiple buds (daughters) simultaneously. Here, we address how mothers partition growth equally among their buds in the multi-budding yeast Aureobasidium pullulans. Bud growth is directed by actin cable networks that appear to be optimized for even partitioning despite complex cell geometries. Even partitioning does not rely on compensatory mechanisms to adjust bud volumes but rather stems directly from effective equalization of polarity sites. These results reveal how conserved cell polarity and cytoskeletal networks are adapted to build complex morphologies in fungi.

  PublisherDOI

Recent grants

• Studies on cell polarity, chemotropism, and cell cycle control

  NIH · $6.1M · 2017–2027

• NIH Grant R01GM079271

  NIH · $4.0M · 2019

• NIH Grant R01GM053050

  NIH · $5.1M · 2013

• NIH Grant R01GM103870

  NIH · $1.8M · 2018

• NIH Grant R01GM062300

  NIH · $5.0M · 2018

Frequent coauthors

• Trevin R. Zyla

  Duke University

  94 shared

• Elaine S.G. Bardes

  Duke Medical Center

  42 shared

• John N. McMillan

  32 shared

• Amy S. Gladfelter

  Duke University

  31 shared

• Timothy C. Elston

  University of North Carolina at Chapel Hill

  30 shared

• Audrey S. Howell

  Howard Hughes Medical Institute

  29 shared

• Steven I. Reed

  28 shared

• Chandra L. Theesfeld

  Princeton University

  26 shared

Labs

• Daniel Lew LabPI

Education

• PhD

  Rockefeller University

  1990

Awards & honors

• Fellow, American Academy of Microbiology (2008)
• Fellow, American Association for the Advancement of Science…
• Duke Equity, Diversity, and Inclusion Award (2019)