Proper formation and growth of the calvaria is critical for the proper accommodation of the growing brain during embryonic and postnatal life. Sustained calvarial bone growth relies on fibrous joints called sutures, which simultaneously act as a barrier between neighboring bones and a source of stem cells to grow bones. In a common congenital abnormality called craniosynostosis, sutures are lost and neighboring bones prematurely fuse, limiting brain growth. In the Farmer lab, we integrate multiple animal models (i.e. mice and zebrafish) with cutting edge genomic, genetic and imaging technologies to decipher the molecular and cellular basis of calvaria development.
Teng CS, Ting MC, Farmer DT, Brockop M, Maxson RE, Crump JG. 2018. Altered bone growth dynamics prefigure craniosynostosis in a zebrafish model of Saethre-Chotzen syndrome. pii: e37024. doi: 10.7554/eLife.37024.
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Organismal form is the product of a complex suite of interacting developmental processes. Variation in these processes allows mammals to adapt to changing environments, but also generates congenital malformations in humans. Developmental variation therefore presents a unifying concept for evolutionary biology and biomedicine, whose understanding is critical to the success of both fields. My primary research goals are to determine how developmental variation interacts with environmental factors within a species to produce congenital malformations in humans, and among species to generate new evolutionary adaptations in mammals. To pursue these goals, I characterize developmental variation across biological scales, and interpret how this variation drives evolution and malformations in form. I incorporate data from fields from paleontology to mathematics to genomics to developmental biology. I also study multiple model and non-model mammals (e.g., mouse, bat, cat, deer, horse, pig, opossum). I use this approach to investigate three major topics: mammalian limb evolution and development, major evolutionary transformations during mammalian evolution, and mammalian sensory system evolution.
As an embryo develops, it needs to generate a myriad of cell types, all in specific locations relative to each other and with correct abundances. Retina, for example, contains more than a hundred neuronal subtypes, organized into three layers of cell bodies and two layers of neuropil. These cell types have different features and frequencies and have to be tiled across the retina in a specific way to support the overall function of the tissue. This seemingly impossible task is accomplished during development with incredible robustness. All the instructions for making this intricate structure, as well as all the other tissues in the body, has to be encoded in the genome. So we hypothesize that the blueprints for making tissues like retina are compressible and involve relatively simple principles. Our goal is to identify these principles and utilize them to develop new therapeutic strategies for neurodegenerative disorders.
Our approach involves imaging based genetic barcoding for tracing the lineage and molecular history of individual cells, spatial transcriptomics for mapping cell states, computational modeling for interpreting the results, and synthetic biology for developing molecular tools to manipulate cell fate decisions.
We are exploring these questions using the embryo of the nematode Caenorhabditis elegans as a model. With a combination of methods drawn from classical genetics, the state-of-the-art in quantitative imaging, and new approaches to manipulating single cells in vivo, we are mapping the emergence of functional circuitry in the embryo. While cell adhesion molecules and morphogen gradients may teach us how to 'wire' a brain, we are working to understand how to 'boot' one up.
Pavak K Shah, Matthew R Tanner, Ismar Kovacevic, Aysha Rankin, Teagan E Marshall, Nathaniel Noblett, Nhan Nguyen Tran, Tony Roenspies, Jeffrey Hung, Zheqian Chen, Cristina Slatculescu, Theodore J Perkins, Zhirong Bao, Antonio Colavita, "PCP and SAX-3/Robo pathways cooperate to regulate convergent extension-based nerve cord assembly in C. elegans", Developmental Cell 41 (2): 195-203 (2017).
We have shown that the 'stemness' of these cells is maintained through the combined action of a Niche Signal, generated by Hedgehog (Hh) (Mandal et al., Nature, 2007), a local signal generated by Wingless/Wnt (Sinenko et al., Dev. Cell., 2009) and a reverse signal from the differentiated cells to the stem cells that we have termed the Equilibrium Signal. Several important concepts underlying Drosophila blood development have allowed us to propose this system as an appropriate genetic model for vertebrate hematopoiesis and these molecular mechanisms are being explored in the laboratory.
4. Metabolic control of early mouse developmentWe also explore the control of metabolic pathways and mitochondrial activity and biogenesis during development using early mouse embryo and the embryonic stem cells derived from them as a model. There is relative lack of data on the mechanisms that control transition between various modes of metabolic activity during phases of development. Nuclear and mitochondrial activities constantly modulate each other, and the relationship between signal transduction pathways commonly studied during development, cancer and stem cell maintenance and metabolic pathways such as oxidative phosphorylation, glycolysis, mitochondrial biosynthesis and nutrient sensing are being explored. Immediate projects include determining the metabolic processes that are essential for zygotic transcription, and the switch between mitochondrial and glycolytic processes during early mouse development.
A Bucksch, A Atta-Boateng, A F Azihou, D Battogtokh, A Baumgartner, B M Binder, S Braybrook, C Chang, V Coneva, T DeWitt, A Fletcher, M Gehan, D H Diaz Martinez, L Hong, A Iyer-Pascuzzi, LL Klein, S A Leiboff, M Li, J Lynch, A Maizel, J N Maloof, RJ C Markelz, C Martinez, L A Miller, W Mio, W Palubicki, H Poorter, C Pradal, C Price, E Puttonen, J Reese, R Rellan-Alvarez, E P Spalding, E E. Sparks, C N Topp, J H Williams, D H Chitwood, "Morphological plant modeling: Unleashing geometric and topological potential within the plant sciences", Frontiers in Plant Science (2017). [link]
The cardiovascular system is the first functioning organ during development. Abnormalities in the formation and/or function of the heart and vessels often lead to embryonic lethality or cause severe health issues in the adult. Our laboratory uses a multidisciplinary approach and the zebrafish model to understand the genetic, molecular and cellular basis of the cardiovascular system during normal development and in diseases.
Our laboratory studies the molecular basis of the skeletal dysplasias, inherited human disorders that affect skeletal development, growth, and maintenance. Our goal is to provide a comprehensive understanding of the genes and gene products that participate in the development of the skeleton and that ultimately determine the shapes of the bones, the height an individual achieves, and the stability of the skeleton. A major step toward achieving our goals is genomic analysis in skeletal dysplasia families to identify the gene associated with each of the over 450 different skeletal dysplasias. For disorders in which the defective gene is known, a combination of mutation analysis and biosynthetic studies is used to understand the mechanisms by which the mutations arise, the inheritance pattern of each disorder, and the effect of each mutation of the synthesis, structure, and function of the encoded protein. These goals are augmented by studies in model organisms, particularly mice, that include mechanistic studies and the development of therapies to ameliorate or cure these disorders.
Egunsola AT, Bae Y, Jiang MM, Liu DS, Chen-Evenson Y, Bertin T, Chen S, Lu JT, Nevarez L, Magal N, Raas-Rothschild A, Swindell EC, Cohn DH, Gibbs RA, Campeau PM, Shohat M, Lee BH, "Loss of DDRGK1 modulates SOX9 ubiquitination in spondyloepimetaphyseal dysplasia", The Journal of clinical investigation 127 (4): 1475-1484 (2017).
Our overall goal is to understand the cell and molecular basis of germline cell differentiation and epigenetic reprogramming. My laboratory uses CRISPR/Cas9 gene editing technologies, next generation sequencing, pluripotent stem cells and mouse modeling to achieve this goal. Results from our work will provide a biological understanding of the cell and molecular basis of human life and child health, and potentially the foundation for a cell based therapy to overcome human infertility.
Because uncontrolled cell division is so dangerous for an organism, cells must know not only when to divide, but?crucially?when not to. Cell division arrest prevents tumors and maintains the proper form of tissues. Many cells must also retain the ability to start dividing again when conditions are right, e.g., when the organism must grow, or a damaged tissue must be repaired. A cell in such a temporary, non-dividing state is said to be ?quiescent.? Quiescence is a common state for many somatic cells, including fibroblasts, lymphocytes, hematopoietic stem cells, and even dormant tumor cells. Failure to appropriately regulate the transition between quiescence and proliferation underlies several common and lethal disorders, including cancer and chronic wounds. My research is focused on understanding the molecular basis of quiescence using in vitro models, mouse models and human patients.
Sullivan WJ, Mullen PJ, Schmid EW, Flores A, Momcilovic M, Sharpley MS, Jelinek D, Whiteley AE, Maxwell MB, Wilde BR, Banerjee U, Coller HA, Shackelford DB, Braas D, Ayer DE, de Aguiar VTQ, Lowry WE, Christofk HR, "Extracellular matrix remodeling regulates glucose metabolism through TXNIP destabilization", Cell 175 (1): 117-132 (2018). [link]
Our laboratory studies the interface of cardiac fibroblasts (scar forming cells) and cardiac progenitors in determining how a cross talk between these cells regulates cardiac repair. We use murine models of cardiac injury and use a variety of fate mapping and conditional knockout strategies to alter specific genes at specific time points after injury to investigate our questions. We study the Wnt signaling pathway, a family of 19 closely related proteins that play key roles in organogenesis, wound healing and cancer. We have recently demonstrated that Wnt1, a Wnt known to play important roles in the development of the central nervous system plays an important role in regulating a fibrotic injury response in the heart. Using transgenic and conditional knock out strategies, we aim to alter the fibrotic repair response of the heart to enable regeneration. 2ff7e9595c
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