The Cell and Developmental Biology Center aims to understand the molecules and the molecular interactions inside cells that build the organelle systems that support basic and specialized functions to control cell fate and behavior. This Center studies how cell behavior guides normal development, including the creation and maintenance of tissues and organs. Researchers combine biochemical, molecular, cellular, genetic, and quantitative approaches to investigate fundamental biological processes across a range of organisms, including fish, flies, mammals, microbes, and viruses. This Center also seeks to apply its basic cell and developmental biological research to the understanding and treatment of human diseases.
The process of directed cellular movement is of critical importance to human health, as is observed when immune cells seek out infected tissues or metastatic cancer cells invade new organs. The Laboratory of Cell and Tissue Morphodynamics, led by Dr. Clare Waterman, has made pioneering discoveries into the complex and dynamic mechanical interactions between organelle systems within cells that are required for directed movement. Dr. Waterman’s laboratory established that the two classes of cytoskeletal polymers—microtubules and filamentous actin (f-actin)—exhibit both direct structural interactions and regulatory interactions mediated by Rho GTPases; it also developed specific technologies, including quantitative fluorescent speckle microscopy (qFSM) to systematically dissect the critical features of these interactions.
Movement of and within cells is fundamental to life, whether in development of an organism, defense against infection, repair after injury, or in pathologies such as cancer and heart disease. Myosin was first identified in skeletal muscle as a motor protein critical to muscle contraction. Two heavy and two pairs of light chains comprise this conventional myosin (now known as myosin II), which polymerizes into filaments to interact with actin and generate force through the hydrolysis of ATP. The Laboratory of Cell Biology is led by Dr. Edward Korn, who has been studying the function and regulation of the actomyosin system in its diverse forms since he discovered the first unconventional non-filamentous myosin, myosin I (containing only a single heavy chain), in the single-cell soil protozoan Acanthamoeba castellanii, approximately forty years ago. Dr. Korn’s laboratory brings the tools of biochemistry and cell biology to focus on three research areas: the role of the actin cytoskeleton in Dictyostelium fruiting body development, the molecular basis of the regulation of actin-activated ATPase activity in myosin II, and the mechanism of association of myosin I with cell membranes.
The primary research interest of the Laboratory of Cellular Physiology, led by Dr. Lois Greene, is in the formation and breakdown of normal and pathological protein complexes in the cell, with an emphasis on the role of molecular chaperones. Dr. Greene studies the role of molecular chaperones and their co-factors in the formation of vesicular compartments from clathrin-coated pits in the cellular membrane during endocytosis. She has applied her wealth of experience in the cell biology of protein folding and membrane trafficking toward deciphering the mechanisms of prion formation and propagation. However, it is becoming increasingly clear that many neurodegenerative diseases—such as Huntington's disease, amyotrophic lateral sclerosis (ALS), and others that are associated with abnormal protein aggregation initiated through genetic mutations—have a prion-like component to their transmission. Once such proteins are misfolded, they may provide a template for other proteins to misfold. Moreover, these misfolded templates could be transmitted between cells. If correct, such a cumulative model of neurodegenerative transmission could partially account for the relatively late onset of these diseases.
Selfish genetic elements distort their own transmission ratio by preferentially segregating to the egg during female meiosis. The Laboratory of Chromosome Dynamics and Evolution, led by Dr. Takashi Akera investigates this non-Mendelian transmission of selfish elements called meiotic drive. Meiotic drive has significant impacts on genetics, evolution, and reproduction, as selfish elements distort transmission ratios and allele frequencies in populations and manipulate gamete production. Dr. Akera’s lab uses the mouse oocyte model to reveal both the cell biological basis and evolutionary consequences of meiotic drive.
Research in the Developmental Neurobiology Laboratory, led by Dr. Herbert M. Geller, focuses on understanding the mechanisms that control axonal growth and pathfinding during neural development and also the mechanisms that stimulate regeneration after injury to the brain or spinal cord. The development of neurons and the neuronal response to injury are influenced by interactions between neurons and the second major cell type in the nervous system, glia. The predominant glial cells in the central nervous system, astrocytes, normally provide a favorable environment for neurons by promoting neuronal migration and the outgrowth of dendritic and axonal processes during development. However, after injury, astrocytes become reactive and form a major part of the glial scar that forms around the injury site and inhibit regeneration. Dr. Geller is identifying the molecular mechanisms at work under these different conditions. His ultimate goal is to promote neuronal regeneration after injury by preventing these changes in astrocytes, adding permissive molecules to astrocytes, or causing neurons to ignore inhibitory cues.
Viruses are experts at exploiting and manipulating the host in numerous and diverse ways throughout their lifecycle. Elucidating these viral mechanisms provides insight into the viral lifecycle and opportunities for therapeutic intervention. It also can provide insight into the host lifecycle, revealing cellular pathways that we did not know existed until viruses were found taking advantage of it. Using cutting edge imaging and spectroscopic technologies combined with novel lipidomic and proteomic approaches, investigations in the Laboratory of Host-Pathogen Dynamics, led by Dr. Nihal Altan-Bonnet, have been at the forefront of understanding the virus-host interface, revealing novel replication and transmission mechanisms shared by many different human viruses. Their investigations are broadly focused on understanding the role of membranes and specifically lipids, in the viral lifecycle.
The Laboratory of Human Endosymbiont Medicine, led by Dr. Neal Epstein, focuses on the further analysis of a novel life form that has been identified by our laboratory to exist within a subset of most all nucleated human cells, forming isolated foci in most tissues. This is distinct from the microbiome as presently studied, which exists on the surfaces of cells, on the skin, and in the gut lumen. The endosymbiont's nucleic acid sequence, physiology, and EM defined morphology show it to be unique with no homologues in GenBank or the literature. A unique antibody shows it is present in the human egg allowing the vertical transmission from mother to progeny as is standard for many endosymbionts in Arthropoda. Facultative free living, it is motile and can be tagged with a fluorescent antibody allowing visualization of it entering human cells in primary culture. The laboratory focuses on its further characterization and its role in human health and disease.
As prototypical cellular motor proteins, most myosins convert the energy of ATP into movement. Contractile muscle myosin II proteins participate in the beating of the heart and movement of the body, while non-muscle myosin IIs play an integral role in cellular movement, shape regulation, and cell division. The Laboratory of Molecular Cardiology, led by Dr. Robert S. Adelstein, is focused on the role of non-muscle myosin II (NM II) in development and disease. Research projects include: the role of NM IIA in spermatogenesis, the function of NM IIs in cardiac development, using whole genomic sequencing to study causative genes for Pentalogy of Cantrell; understanding the role of NM IIA in squamous cell carcinoma; NM II and mechanotransduction; and studying the functions of the Rbfox family of RNA binding proteins.
The primary research interests of the Molecular Cell Biology Laboratory, led by Dr. John A. Hammer, revolve around the roles played by motor proteins and cytoskeletal protein dynamics in driving the motility of organelles and cells. The inside of a living cell is not a still place. From the motor protein-dependent transport of organelles inside the cell, to the changes in overall cell shape driven by cytoskeletal dynamics, normal cell function is highly dependent on movement. Dr. Hammer’s lab uses cell biological, genetic, biochemical, and biophysical approaches, coupled with advanced imaging techniques, to study the molecular interactions that give rise to cellular and intracellular movements, and to define the functional significance of these movements in the context of whole organisms. Recently, Dr. Hammer has focused more efforts on understanding the role played by cytoskeletal protein dynamics in driving the proper function of certain white blood cells called T lymphocytes.
The Laboratory of Molecular Machines and Tissue Architecture, led by Dr. Nasser M. Rusan, studies the role of centrosomes during animal development. The centrosome is a non-membrane bound organelle that serves as the main microtubule (MT) organizing center of most animal cells. Centrosomes function to initiate and maintain cell polarity, guide cell migration, direct intracellular cargos, and properly distribute other organelles. In mitosis, or cell division, centrosomes are critical for accurate construction of the mitotic spindle to ensure faithful chromosome separation to the two daughter cells. Thus, it is not a surprise that defects in centrosome function lead to a wide range of failures at the cellular level, which in turn, leads to tissue defects and many human diseases. The lab aims to determine how centrosomes are properly constructed from their individual parts and how centrosomes function in a wide range of cell types to avoid human diseases such as polycystic kidney disease, microcephaly, and cancer.
Early work in the Laboratory of Molecular Physiology, led by Dr. James R. Sellers, focused on the regulation of the myosin II isoforms found in smooth muscle and non-muscle cells. Myosins are cellular motor proteins. As new myosin isoforms were discovered, his interests shifted to also include studies of these “unconventional” myosins. Dr. Sellers has focused on studying myosin diversity as a means of understanding meaningful molecular differences that give rise to disparate functions. His interdisciplinary laboratory brings together a breadth of experience in fields such as developmental biology, biochemistry, cell biology, biophysics, and engineering and encompasses studies of systems ranging from single molecules to fruit fly models (Drosophila melanogaster).
The selective recycling of lipids and proteins is critical to healthy cellular function. Many genes associated with human diseases encode components of the cellular machinery that sorts lipids and proteins for selective trafficking along endocytic pathways leading to lysosomal degradation. The Laboratory of Protein Trafficking and Organelle Biology, led by Dr. Rosa Puertollano, seeks to understand precisely how defects in intracellular trafficking—specifically, in endosomal and lysosomal pathways—contribute to human diseases.
The overarching goal of the Laboratory of Stem Cell and Neurovascular Research, led by Dr. Yoh-suke Mukouyama, is to uncover the molecular control of the morphologic processes underlying the branching morphogenesis and patterning of the vascular and nervous systems. These systems share several anatomic and functional characteristics and are often patterned similarly in peripheral tissues. These characteristics suggest that there is interdependence between these two networks during tissue development and homeostasis. Thus, Dr. Mukouyama is studying neuronal influences on vascular branching patterns and vascular influences on both neuronal guidance and neural stem cell maintenance. He has recently extended the lab’s research to the unanticipated roles of tissue macrophages and microglia in neuronal and vascular development. His laboratory approaches these problems using a combination of high-resolution whole-mount imaging, advanced genetic perturbations, and in vitro organ culture techniques.
The laboratory of Structural Cell Biology aims to understand the molecular mechanisms governing specialized cell shapes, such as those of neurons, activated immune cells or platelets and certain cancer cells. We visualize the key factors determining different cell morphologies using in situ cellular cryo-electron tomography in combination with interdisciplinary techniques such as single-particle cryo-EM, X-ray crystallography, in vitro reconstitution and light microscopy.