About

Mary C. Mullins, Ph.D., is a Professor of Cell and Developmental Biology at the University of Pennsylvania's Perelman School of Medicine. Her research focuses on the molecular mechanisms by which the Bone Morphogenetic Protein (BMP) signal transduction pathway establishes different aspects of the vertebrate body plan. She studies the formation, function, and regulation of BMP activity gradients, which are implicated in the specification of diverse cell types along the dorsal-ventral axis, neural crest specification, and dorsal-ventral patterning of neural tissue. Her work also explores the role of BMP signaling in post-embryonic heart development and its misregulation in human disease, such as fibrodysplasia ossificans progressiva (FOP). Dr. Mullins has performed large-scale maternal-effect mutant screens in zebrafish to identify genes required for oocyte development, egg activation, fertilization, and embryonic axis formation, and she investigates the molecular and cellular basis of these processes. Her research employs zebrafish mutants, antisense knockdowns, and mathematical modeling to dissect the molecular activities of BMP receptors and the maternal control of embryonic development.

Research topics

• Medicine
• Family medicine
• Internal medicine
• Nursing

Selected publications

• Sample 3D confocal stacks for the Oocyte_Surface_Pipeline (zebrafish, cyclinB1 / dazl)

  Zenodo (CERN European Organization for Nuclear Research) · 2026-04-29

  datasetOpen access

  Three representative 3-channel confocal z-stacks of stage I/II zebrafish oocytes, one per genotype (WT, Δ6, Δ6+11), used as sample input for the Oocyte_Surface_Pipeline (https://github.com/jzinski/Oocyte_Surface_Pipeline). Channel 1: oocyte outline (DAPI). Channel 2: cyclinB1 (HCR). Channel 3: dazl (HCR). Voxel size: xy = 0.3321 µm, z = 2.6 µm. Format: multi-page TIFF, 3 channels interleaved per Z slice. Files: WT_dazl_cyclinB1_10.tif (wild type) d6_dazl_cyclinB1_14.tif (Δ6) d6+11_dazl_cyclinB1_19.tif (Δ6+11)

  PublisherDOI

• EpicTope: predicting and validating non-disruptive epitope tagging sites

  Development · 2026-03-01

  articleOpen accessSenior author

  Epitope tagging is a valuable technique enabling the in vivo identification, tracking and purification of proteins. We developed a tool, EpicTope, to facilitate this method by identifying amino acid positions most suitable for epitope insertion. Our method uses a scoring function that considers protein sequence secondary and tertiary structural features, solvent accessibility, and disordered binding regions to determine locations least disruptive to the protein function. We validated our approach on the zebrafish Smad5 and Hdac1 proteins. We show that multiple predicted internally tagged Smad5 proteins rescue zebrafish smad5 mutant embryos, while the N- and C-terminal-tagged variants do not, as predicted. Similarly, we found that optimally predicted internal and C-terminal Hdac1 tags rescued hdac1 mutant embryos, while a less-optimal N-terminal tag did not. We further show that these functionally tagged Smad5 and Hdac1 proteins are accessible to antibodies in whole-mount zebrafish embryo immunofluorescence, by western blotting and by immunoprecipitation from embryo extracts. Our work demonstrates that EpicTope is an accessible and effective tool for designing epitope tag insertion sites.

  PublisherDOI

• Sample 3D confocal stacks for the Oocyte_Surface_Pipeline (zebrafish, cyclinB1 / dazl)

  Open MIND · 2026-04-29

  datasetOpen access

  Three representative 3-channel confocal z-stacks of stage I/II zebrafish oocytes, one per genotype (WT, Δ6, Δ6+11), used as sample input for the Oocyte_Surface_Pipeline (https://github.com/jzinski/Oocyte_Surface_Pipeline). Channel 1: oocyte outline (DAPI). Channel 2: cyclinB1 (HCR). Channel 3: dazl (HCR). Voxel size: xy = 0.3321 µm, z = 2.6 µm. Format: multi-page TIFF, 3 channels interleaved per Z slice. Files: WT_dazl_cyclinB1_10.tif (wild type) d6_dazl_cyclinB1_14.tif (Δ6) d6+11_dazl_cyclinB1_19.tif (Δ6+11)

  PublisherDOI

• Modeling epithelial deformation and cell rearrangement in response to external forces during Zebrafish epiboly

  npj Systems Biology and Applications · 2026-04-21

  articleOpen access

  Morphogenesis in early development involves complex and extreme deformations in response to intra- and intercellular forces. Zebrafish epiboly, the spreading of the blastoderm to cover and engulf the large yolk cell, is a key early event that sets the stage for the establishment of the body plan, but the way the forces driving expansion are generated and mediated is poorly understood. The enveloping layer (EVL), the thin squamous outer epithelium of the blastoderm, plays a central role. Forces generated in the yolk cell are transmitted through tight junctions to the marginal EVL cells, and then propagate through the rest of the EVL. To understand mechanisms of force generation and transduction during epiboly, we first need a mechanical model of the EVL capable of responding to such forces and undergoing the drastic deformation of epiboly. The expanding EVL more than doubles its surface area and experiences significant shear as it deforms from a thin cap at one pole to become a complete sphere, necessarily requiring extensive internal rearrangement. We constructed an agent-based model of the EVL and its response to exogenous forces using the center-based simulation framework, Tissue Forge. Our model captures the large viscoelastoplastic deformation of the EVL by cell rearrangement, and accommodates the required cell neighbor exchanges without losing mechanical integration. Features observed in living embryos, such as the straightening of the initially ragged leading edge, also emerge in the model. We identified two key components required for realistic epiboly in the model: first, a mechanism to enable tissue remodeling by cell rearrangement without tearing the tissue, and second, a negative feedback on the forces driving EVL expansion, to regulate and synchronize the advancement of the EVL margin. We discuss the implications of these findings for the behavior of living EVL and the mechanisms that drive epiboly.

  PublisherDOI

• Not all dimers are equal

  eLife · 2025-05-02

  editorialOpen accessSenior author

  Disease-causing mutations in the signaling protein BMP4 impair its secretion, but only when it is made as a homodimer.

  PublisherDOI

• Rules of Life at the Interface of Calcium Signaling and Mechanobiology

  Preprints.org · 2025-06-05

  preprintOpen access

  Living systems process a broad range of internal and external stimuli, respond to environmental constraints, and adapt to various conditions. The functional interactions between components and mechanisms operating at each scale - from molecules to organisms - define the collective “Rules of Life” (RoLs) that govern the emergent properties of biological systems. This review highlights calcium ions (Ca2+), key signaling mediators, which serve as core integrators by facilitating the organization and emergence of structure and function through information encoded in its dynamics. Despite its diverse roles, calcium signaling follows consistent and conserved principles that establish regulatory RoLs that operate across various biological contexts. Here, we examine the key components and functional interactions at the interface of calcium signaling and cellular responses, focusing on calcium-cytoskeleton coupling—how calcium signaling regulates and is regulated by cytoskeletal dynamics. Throughout, we emphasize the importance of computational modeling for the integration of large scale biological data and propose defined RoLs as a modular framework to efficiently capture emergent, multiscalar dynamics of cellular and tissue mechanics across diverse systems. We introduce three RoLs: i) Ca2+ directs cytoskeletal reorganization following stress and damage, ii) Ca2+ modulates actin dynamics to control synapse-like processes across neuronal, immune, and fertilization contexts, and iii) Ca2+ exhibits diverse spatial patterns that both influence and reflect cellular function, contributing to role-specific behaviors. Finally, we address current limitations in integrating cell responses and calcium signaling and outline future directions to develop predictive computational models that unify chemical signaling with cellular organization, including translational applications.

  PublisherOA PDFDOI

• Forming a Complex: Turbocharging BMP Signal Activation by Heterodimeric Ligands and Heteromeric Receptor Complexes

  Annual Review of Genetics · 2025-08-08

  reviewOpen accessSenior author

  Bone morphogenetic protein (BMP) signaling functions in a vast range of biological contexts. The basic signaling mechanism of this pathway is well-defined, with BMP ligand dimers recruiting tetrameric receptor complexes that phosphorylate Smads to regulate gene expression. Research has found that the mechanism of BMP signal activation may not be as simple as this linear relay, specifically in considering signal activation by ligand homodi-mers versus heterodimers. Focusing largely on in vivo vertebrate contexts, we discuss how BMP heterodimers exhibit enhanced or exclusive signaling over homodimers, demonstrating that not all signal inputs are functionally equivalent. Challenging the notion that ligand-receptor binding affinity is the primary driver of signal activation, we highlight evidence that some receptors do not signal even when high-affinity ligands are present. Further, not all receptors in the signaling complex are equal, with the kinase activity of some being dispensable while others are obligatory. These observations shift the focus of BMP signal activation to mechanisms by which heterodimeric ligands with specific receptor combinations facilitate signal outcomes in different contexts.

  PublisherDOI

• Oocyte polarity is established independently of the Balbiani body

  bioRxiv (Cold Spring Harbor Laboratory) · 2025-08-27 · 1 citations

  preprintOpen accessSenior authorCorresponding

  ABSTRACT In most animals, oocyte polarity establishes the embryonic body plan by asymmetrically localizing axis-determining transcripts. These transcripts first localize in Xenopus and zebrafish oocytes to the Balbiani body (Bb), a large membrane-less organelle conserved from insects to humans. The Bb is transient, disassembling and anchoring at one pole the axis-determining transcripts that establish the vegetal pole of the oocyte. Aggregation of the Bb depends on the Bucky ball (Buc) protein, an intrinsically disordered protein with a prion-like self-aggregation domain. In zebrafish buc null mutants, the Bb fails to form and oocytes lack polarity. Here, we established buc hypomorphic mutants that fail to form the Bb, but remarkably Buc protein and vegetal mRNAs localized normally at the vegetal cortex of the oocyte. Thus, these buc hypomorphic mutants displayed normal oocyte polarity, demonstrating that the Bb is not required to establish oocyte polarity. We found that both a reduced Buc protein level and truncation of the N-terminal 10 amino acids contribute to Bb failure in the hypomorphic mutants.

  PublisherOA PDFDOI

• Zebrafish armc9 mutant reveals a link between ARM-Type fold domain loss, inflammation, and spinal curvature

  bioRxiv (Cold Spring Harbor Laboratory) · 2025-04-03

  preprintOpen access

  The vertebral column (VC) defines the central axis of vertebrates. Among its malformations, adolescent idiopathic scoliosis (AIS) is the most common, characterized by lateral spine curvature without congenital abnormalities. While its etiology remains elusive, genetic studies in zebrafish have linked AIS to skeletogenesis, cilia structure, cerebrospinal fluid flow, and inflammation. In this study, we characterized the zebrafish armc9 mutant, exhibiting AIS-like curvature without vertebral malformations, subcommissural organ, or Reissner fiber structure disruptions. We also detected an inflammatory response at the curvature origin. Structural bioinformatics and molecular docking analyses suggest that the mutant Armc9 protein partially lacks the functional ARM-type fold domain, which is crucial for its interaction with Togaram1, revealing that both proteins are relevant for ciliary signaling and spine curvature. Phylogenetic analyses indicate that the ARMC gene family encompasses 12 members, highlighting that the Armc9 gene has deep evolutionary roots. Our results demonstrate that the zebrafish armc9 mutant accurately represents the AIS phenotype, suggesting that the loss of Armc9's C-terminal ARM-type fold domain could affect the ciliary integrity and contribute to spine curvature by altering the skeletogenic environment. Taken together, this study proposes that the zebrafish armc9 mutant offers a unique opportunity to understand the etiology of AIS and provides new insights into the molecular interaction networks of Armc9 in ciliary signaling.

  PublisherDOI

• Acvr2b receptors transduce all BMP signaling in the zebrafish gastrula and restrict Fibrodysplasia Ossificans Progressiva ACVR1-R206H signaling in a dose-dependent manner

  bioRxiv (Cold Spring Harbor Laboratory) · 2025-10-07

  preprintOpen accessSenior authorCorresponding

  ABSTRACT BMP signaling drives dorsoventral (DV) axial patterning in vertebrates and invertebrates, with BMP dimers recruiting tetrameric receptor complexes to phosphorylate SMADs that activate ventral target gene expression. In zebrafish DV patterning, BMP2/7 heterodimers exclusively signal, assembling a receptor complex of two distinct type I receptors, Bmpr1 and Acvr1l, that canonically bind Bmp2 and Bmp7 ligands, respectively. We tested if the two distinct classes of BMP type II receptors, Bmpr2 and Acvr2, also act in the signaling complex. We determined that Acvr2 receptors solely transduce BMP signaling in DV patterning. We mutated all four acvr2a and acvr2b genes in the zebrafish and found that maternal-zygotic depletion of just Acvr2b receptors abrogates all BMP signaling, indicating that Acvr2b is the primary type II receptor transducing BMP signaling in the gastrula. We further demonstrated that hyperactive signaling through the ACVR1-R206H Fibrodysplasia Ossificans Progressiva human disease-causing mutant receptor is restricted when maternal and zygotic contributions of either Acvr2ba or Acvr2bb are absent. This reveals an increased sensitivity of ACVR1-R206H signaling to Acvr2b dosage, compared to wild-type ACVR1. These findings support a model in which Acvr2b receptors mediate the endogenous BMP signaling in the gastrula and that hyperactivity of ACVR1-R206H is limited in a dose-dependent manner by the relative concentration of Acvr2b.

  PublisherOA PDFDOI

Recent grants

• NIH Grant R01GM056326

  NIH · $6.6M · 2020

• NIH Grant R01HD050901

  NIH · $1.9M · 2010

• NIH Grant R21HD062952

  NIH · $425k · 2012

• NIH Grant R01GM05632615S1

  NIH · $97k · 2016

• NIH Grant R01GM117981

  NIH · $1.4M · 2019

Frequent coauthors

• Michael Granato

  University of Pennsylvania

  42 shared

• Matthias Hammerschmidt

  University of Cologne

  41 shared

• Christiane Nüsslein–Volhard

  Max Planck Institute for Biology

  39 shared

• Pascal Haffter

  Max Planck Institute for Developmental Biology

  39 shared

• Carl‐Philipp Heisenberg

  38 shared

• Yun‐Jin Jiang

  National Health Research Institutes

  37 shared

• Robert N. Kelsh

  University of Bath

  36 shared

• Michael Brand

  TU Dresden

  36 shared

Labs

• Mullins LabPI