Developmental Biology

Development and Disease Mechanisms

Faculty, fellows and students in the Department of Developmental Biology are working at the forefront of basic science research to understand the principals and molecular mechanisms that guide embryonic development, the differentiation of adult cell types, regeneration, and aging. This work is related to a number of human diseases. Further information about how work in our department is contributing to the fundamental understanding of disease mechanisms is given on the research milestones and what is DevBio pages.

Disease Mechanisms & Faculty Interest Areas

Ben Barres, M.D.
Regeneration, Spinal cord injury, Multiple Sclerosis, Paralysis, Glaucoma, Alzheimer's disease

Why does the brain fail to regenerate and repair itself after injury? Unlike most of our body parts, when our brain or spinal cord is injured, little regeneration and repair occurs. In our lab we are investigating the basis of this regenerative failure. It has long been known that the developing nervous system has a relatively good abililty to repair itself, but that this ability is lost with maturation to adulthood. The Barres laboratory has developed novel methods to purify brain neurons and to study their behavior in culture. Recently, the Barres group used these methods to compare the ability of young and old neurons to regenerate, and discovered that the old neurons regenerate their axons 10 times more slowly than do young neurons. This was a surprise because it has long been thought that poor growth ability of the old neurons was caused by inhibition by glial cells present in the mature brain. These results show that a major part of the problem is intrinsic to neuron maturation itself. The Barres lab is currently using genomic methods to elucidate the molecular basis of this loss of axon regeneration ability. The answers should provide novel targets to develop drugs that induce rapid regeneration.

Gerald Crabtree, M.D.
Neural development, Downs' syndrome, Cardiovascular development and disease, Immunodeficiency and autoimmune disease, Allergy and asthma, cancer, Gene therapy

The Crabtree laboratory is studying the molecular mechanisms underlying the development of the vertebrate nervous and immune systems. Recent work from their laboratory has shown that signaling by calcineurin and NFAT play essential roles in lineage determination of neurons and later roles in guiding axons to their eventual destinations. In adults vertebrates this signaling pathway is essential for learning and memory and recent human genetic evidence has implicated it in both schizophrenia and Down's syndrome. The Crabtree lab has identified a number of modulators of NFAT signaling and they are working to understand how they function in the normal and pathologic development of the nervous system.

To better understand developmental mechanisms the laboratory has been devising rapid and reversible ways to control the activity of genes during development by controlling the activity of the proteins they encode using small molecules. In this work they are producing small molecules capable of disrupting protein-protein interactions and also molecules that regulate the activity of chimeric proteins for use in developmental mechanistic studies as well as human gene therapy.

An additional area of interest in Dr. Crabtree's laboratory is the role of ATP-dependent chromatin remodeling complexes in development. One of these, the BAF complex acts downstream of many developmental signaling pathways, including NFAT, to control lineage specification and perhaps stem cell renewal. These complexes contain actin and in some mysterious way regulate higher order chromatin structure. Dr Crabtree's laboratory discovered that the SWI/SNF-like BAF complex acts as a tumor suppressor and later work demonstrated that certain childhood malignancies are due to deletion of one of its subunits.

Margaret T. Fuller, Ph.D.
Stem cells, regeneration, cancer, infertility.

Dr. Fuller’s laboratory investigates the mechanisms that regulate proliferation, differentiation and self-renewal of adult stem cells in vivo. Understanding the fundamental mechanisms that regulate normal adult stem cell behavior in the body may provide key strategies for growth, amplification and manipulation of adult stem cells in the laboratory in preparation for clinical use for tissue regeneration, or gene therapy. Dr. Fuller’s group has recently demonstrated that the microenvironment provided by support cells plays a critical role in regulation of stem self-renewal and maintenance in vivo. Particularly exciting is her laboratory’s identification of the signaling molecules that specify stem cell self-renewal, as these ligands can now be tested for ability to signal stem cell proliferation and expansion of stem cell populations in vitro.

A second focus of Dr. Fuller’s research explores how the developmental program regulates the cell cycle. During development of an embryo, tissue or organ, it is critical that cells divide on schedule and stop dividing when they are supposed to. Failure of precursor cells to stop dividing and initiate differentiation is an early step on the road to cancer. Dr. Fuller’s group studies the molecular mechanisms that regulate cell cycle progression and the defects that lead to cell cycle arrest or precursor cell overproliferation during the developmentally programmed cell cycle of male meiosis. Most strikingly, Dr. Fuller’s group has identified important checkpoint pathways that coordinate cell cycle progression with the expression of terminal differentiation genes. In addition, Dr. Fuller’s laboratory is utilizing a genetic approach to identify key genes and molecular mechanisms that mediate and regulate cytokinesis, the final step in cell division.

Dr. Fuller’s group also uses the laboratory fruitfly Drosophila to investigate the molecular and genetic causes underlying meiosis I arrest male infertility. Dr. Fuller’s work has established as a paradigm that spermatogenesis requires the action of specialized forms of the basic transcription machinery. Testis-specific components of the general transcription machinery have now been shown to be utilized for spermatogenesis in man and required for normal male fertility in mouse.

Dale Kaiser, Ph.D.
Organ formation, Birth defects, Skeletal development, Cell-cell communication and morphogenesis

Dr. Kaiser’s laboratory investigates bacterial development to understand basic molecular mechanisms through which cells communicate and cooperate to form and pattern multicellular structures, as in organ formation and embryonic development in higher anamals. How does cell movement build a structure? How are morphogenetic movements coordinated by interactions between cells or cues from extracellular materials? These questions underlie and motivate Dr. Kaiser’s research on Myxobacteria. Masses of myxobacterial cells move in ways that are striking for their organization. Although each cell can move on its own, groups of 5 - 50 cells temporarily associate to move as raft-like units. Also, 100,000 cells assemble in species specific ways to form their fruiting bodies. Different species of myxobacteria give rise to fruiting bodies of characteristically different form, showing that the underlying patterns of cell movement are inherited. Morphogenesis of fruiting bodies is facilitated by gliding motility which permits cells to move over each other and thus to build a complex three-dimensional structure. The fruiting bodies of Stigmatella and Chondromyces, for example, have a tall stalk surmounted by multiple, spore-containing macrocysts. The assembly of motile myxobacterial cells into a fruiting body of particular shape and size, followed by the differentiation of spores, has striking parallels to the early stages of human skeletal development. In skeletal development, cells of the dorsal mesoderm migrate, signal to each other and assemble into concentrates that eventually become pieces of bones, tendons, connective tissue, and muscle. Because of this basic parallel, fruiting body development may yield insights into molecular mechanisms underlying human skeletal abnormalities arising as consequences of abnormal development.

Seung K. Kim, Ph.D.
Diabetes, Stem cells, Birth defects, Tissue regeneration

Dr. Kim’s laboratory investigates the mechanisms that regulate formation and function of the pancreas. Dr. Kim’s studies are identifying key cell-cell signaling pathways and master regulatory genes that control morphogenesis and cell differentiation of the pancreas during embryonic development and growth and function of the pancreas in adults. The molecular pathways that mediate and regulate organ formation during development are the best candidates for strategies that can be harnessed to specify regeneration of damaged or lost tissue. Using this approach, Dr. Kim’s laboratory has become one of the world leaders in the effort to use embryonic stem (ES) cells to develop novel strategies for islet cell replacement in type I diabetes mellitus.
Dr. Kim’s research also employs the powerful genetic and genomic approaches available in the laboratory fruitfly Drosophila to investigate the regulation and function of the insulin pathway in growth regulation, development and homeostasis. As there are many parallels between Drosophila and humans in the role and regulation of the insulin pathway, Dr. Kim’s work is providing important insights into how this critical hormone modulates development, behavior, nutritional homeostasis and aging, and how the production and action of insulin is controlled in the body.

Stuart K. Kim, Ph.D.
Aging, Diabetes, Cancer

Aging is among the most universal of biological processes and perhaps also among the most mysterious. Numerous age-related changes are apparent at the organismic level, but we are only now starting to understand age-related changes at the molecular level. Oxidative damage, replicative senescence, accumulated stress and metabolic rate have each been proposed to specify life span. Dr. Stuart Kim’s laboratory is using functional genomics approaches to uncover the underlying genetic networks that determine longevity in the nematode C. elegans, an excellent model organism in which to study aging. The normal life span for worms is 2 weeks but under poor growth conditions, worms enter the dauer state and have life spans that can be 10 times longer. Powerful genetic screens have been used to identify mutants with increased life span. In particular, loss-of-function mutations in genes in the C. elegans insulin signaling pathway (such as daf-2 insulin receptor and age-1 PI3 kinase) extend life span. These results indicate that insulin signaling plays an important role in specifying life span, probably by regulating rates of cellular metabolism. Although previous genetic experiments have identified upstream regulatory pathways that influence the rate of aging, metabolic processes and genetic pathways that lie downstream of the insulin signaling pathway and that directly influence cellular senescence and organismic longevity are poorly understood.

To identify terminal effector genes that may directly influence life span, Dr. Kim’s group is using DNA microarrays containing nearly every gene in C. elegans to profile gene expression changes during normal life span, during the dauer stage and in mutants with increased longevity. In analyzing these gene expression patterns, Dr. Kim seeks to identify common genetic mechanisms involved in specifying life span. A surprising result is that Dr. Kim’s preliminary studies found only 164 aging-regulated genes from an extensive microarray analysis of gene expression changes during the normal life span. This result indicates that gene expression in old worms is relatively stable. The 164 aging-regulated genes include two insulin-like genes and a sir-2 homolog that increase at the end of life. Previous studies have shown that insulin signaling and sir-2 regulation act to specify life span in C. elegans. Heat shock genes decrease in old age, possibly resulting in increased levels of protein denaturation, decreased cell function and organismal senescence.

David Kingsley, Ph.D.
Arthritis, Bone formation and healing, Skeletal development, Genetic mechanisms of adaptation in evolution

Dr. Kingsley's lab studies the genetic basis of bone and cartilage formation. His studies have identified a key family of secreted signaling molecules used to induce bone and cartilage formation during embryogenesis. These same signals molecules are reactivated in adult animals during repair of bone fractures. This work provides an excellent example of how the pathways used to stimulate tissue formation in embryos are also critical for repair and regeneration of tissues in adults. Dr. Kingsley's work has also identified novel molecules that control both formation and maintenance of synovial joints. These studies have revealed a novel pathway that normally protects the joints of higher animals from mineral deposition and arthritis. Mutations in this pathway lead to hereditary forms of arthritis in both mice and humans. Manipulating the activity or level of this pathway may provide new strategies for preventing some forms of joint disease in humans. Finally, Dr. Kingsley has pioneered the use of new model systems to study the genetic basis of vertebrate biodiversity and response to global climate change. His work with stickleback fish is uncovering the genomic and genetic basis of dramatic changes in both skeletal and physiological characteristics in different species. This work will provide a new understanding of how organisms adapt to changing conditions, and how basic developmental pathways can be modified to obtain useful changes in both structure and function of higher animals.

Harley McAdams, Ph.D.
Bacterial pathogenicity, Design of new antibiotics, Cancer

Dr. McAdams’ group works on fundamental properties of the genetic regulatory circuits that control how cells function. These circuits include switches that respond to signals from the cell's environment and oscillatory circuits that control the cell cycle. Many infective bacteria depend on proper functioning of such switches for success in growing within the bodies of their target hosts, including humans. By understanding the details of these control circuits at the level of their detailed chemistry and physics, Dr. McAdams’s group seeks to identify places where new antibiotics could disrupt the infective process or kill the bacteria. Dr. McAdams pioneered studies that showed how random events in the fundamental chemistry of the genetic machinery of cells could affect the macroscopic behavior and health of cells. Now it is becoming widely recognized that these so called "stochastic mechanisms" are important in many bacterial virulence mechanisms and probably even play a role in early events that start healthy human cells on the path to becoming cancer cells.

Roel Nusse, Ph.D.
Cancer, Stem cells, Birth defects, Neural regeneration

Our laboratory is interested in the growth, development and integrity of animal tissues. We study multiple different organs, trying to identify common principles, and we extend these investigations to cancer and injury repair. In most organs, different cell types are generated by stem cells - cells that also make copies of themselves and thereby maintain the tissue. An optimal balance between the number of stem and differentiated cells is essential for the proper function of the organs. Locally-acting signals are important to maintain this balance in a spatially-organized manner and these signals are key to understanding the regulation of growth.

A common theme linking our work together are Wnt signals. Work from many laboratories, including our own, has shown that Wnt proteins are essential for the control over stem cells. How this is achieved is far from clear and is the subject of studies in the lab, both in vivo and in cell culture. In vivo, a particular question we address is how physiological changes, such as those occurring during hormonal stimuli, injury or programmed tissue degeneration have an impact on the self-renewal signals and on stem cell biology. See website:

Matthew Scott, Ph.D.
Cancer, Birth defects, Brain development, Neural stem cells

Dr. Scott’s laboratory investigates the master regulatory HOX genes and the cell-cell communication pathways responsible for setting up normal body pattern, organ formation, skin and hair development, and brain and heart development in the early embryo. Dr. Scott’s work on the Hedgehog (Hh) signaling pathway has revealed the genetic and molecular basis for the most common form of human cancer, basal cell carcinoma of the skin, as well as the childhood brain cancer meduloblastoma. Dr. Scott’s laboratory is utilizing genetic approaches in the laboratory fruitfly Drosophila to investigate the mechanism of how Hedgehog signaling acts and how this critical signaling pathway is regulated in normal development and in disease. Following up on his discoveries of the role of the critical negative regulator of Hedgehog signaling, Ptc, Dr. Scott’s group is investigating the molecular basis of the human neurodegenerative disease Niemann-Pick type C1 (NPC1), which is caused by defects in a protein related to Ptc. In addition, Dr. Scott’s group is utilizing a combined genomics and genetic approach in mammals and zebrafish to investigate the mechanisms that regulate proliferation and differentiation of neural stem cells in the brain and that specify normal development of the cerebellum.

Lucy Shapiro, Ph.D.
Cell cycle regulation, Asymmetric cell division, Design of novel antibiotics, Gene regulatory networks

Dr. Shapiro’s research investigates the mechanisms that coordinate cell differentiation and the cell cycle using as a model system the bacterium Caulobacter. Dr. Shapiro’s pioneering studies have shown that cyclic phosphorylation cascades and proteolysis regulate cell cycle progression in bacterial cells, and in higher organisms. Dr. Shapiro’s group made the striking discovery that specific regulatory proteins and chromosomal regions undergo dynamic and stereotyped changes in subcellular localization during cell cycle progression. Utilizing the power of facile genetics and genomics available in the bacterial system, Dr. Shapiro’s group is rapidly discovering key regulatory mechanisms that govern asymmetric cell division, cell cycle progression, and the coordination of the cell cycle and cellular differentiation programs. The knowledge of bacterial development and genomics that Dr. Shapiro’s research has generated has allowed her laboratory to develop novel strategies for the design of new antibiotics, an acute medical need to combat the worldwide rise of antibiotic resistant strains of pathogenic microorganisms.

William Talbot, Ph.D.
Multiple Sclerosis, Birth defects, Brain development, Neural degeneration and regeneration

Myelin, the white matter that insulates and protects nerves, is essential for the efficient conduction of nerve impulses. Myelin is damaged by disease processes such as Multiple Sclerosis. At the cellular level, damage to myelin disrupts the conduction of nerve impulses and leads to the loss of nerve fibers. There are still no effective therapies for the recovery of function in regions of the brain and spinal cord that have been damaged by demyelination. Successful treatment of Multiple Sclerosis may require the use of therapies that promote regeneration of myelin. Dr. Talbot’s laboratory uses a combined genetic, cellular, and molecular approach to investigate the genes that govern the formation of myelinated nerves in zebrafish, a vertebrate model organism amenable to large-scale genetic studies. The Talbot group has identified zebrafish mutations that reduce or disrupt myelin production. Dr. Talbot’s laboratory is characterizing these mutants to learn how the mutated genes function to promote the normal development of myelin and mapping the mutations to identify the genes that are responsible. Dr. Talbot’s studies will identify the molecular pathways that trigger myelin formation. The analysis of zebrafish mutants will lead to new animal models of diseases of myelin. Dr. Talbot’s research program on myelination is providing information about basic mechanisms that may lead to the development of new therapies for diseases of myelin, including Multiple Sclerosis.

Anne Villeneuve, Ph.D.
Birth defects, Downs’ syndrome, infertility, Repair of DNA damage, Cancer, Aging

Dr. Villeneuve’s research investigates underlying chromosomal mechanisms that lead to miscarrage, birth defects and Down’s syndrome, cancer and aging. Using the nematode roundworm Caenorhabditis elegans as a powerful genetic model system, Dr. Villeneuve’s group is discovering the mechanisms by which chromosomes reliably pair, recombine and properly segregate during meiosis. These events are of central importance to sexually reproducing organisms, since defects result in embryos that receive an abnormal number of chromosomes. Dr. Villeneuve’s innovative work has been responsible for the emergence of C. elegans as a major model system for investigating the mechanisms underlying meiotic chromosome behavior. Dr. Villeneuve’s laboratory is also investigating how organisms protect themselves from DNA damage. Whether damage is incurred through exposure to environmental mutagens or arises spontaneously, organisms depend on their capacity to recognize DNA damage and either repair it or eliminate the damaged cells. Failure can lead to the development of cancer, and defects in the ability to repair DNA accurately are responsible for several inherited human cancer syndromes. Accumulation of DNA damage is also postulated as a major factor driving the aging process. Dr. Villeneuve’s laboratory is using the genetic and genomics power of the C. elegans system to identify new components of the DNA repair machinery, to investigate the roles of these components in genome maintenance, and to explore the involvement of these DNA repair mechanisms in aging.

Irving Weissman, M.D.
Stem cells, cancer, neural regeneration, immune system function

Dr. Weissman’s laboratory investigates the purification, biology, transplantation, and evolution of hematopoietic, germ line and neural stem cells. Dr. Weissman is a world leader in stem cell biology. His group studies mechanisms that regulate and mediate differentiation of blood cell types from hematopoietic stem cells, the mechanisms of homing, competition and colonization by exogenously introduced stem cells, and the role of programmed cell death in leukemia. Dr. Weissman’s work on the immune system and cancer is revealing mechanisms that regulate differentiation of T and B cells, lymphocyte homing, lymphoma invasiveness and metastasis.

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