For You
|
||||||||||||
(301) 402-6690
(301) 496-7184 
Dr. Feldman utilizes genomic, molecular and developmental biology strategies to investigate gastrulation in zebrafish. Written in the genomes of multi-cellular organisms are instructions for a remarkable series of tasks. First, the organism must self-assemble, transitioning from a single cell to a fully formed adult. Second, the organism must keep its physiology in working order. Finally, from the first cell division onward, the outputs of each cell's genome must be coordinated, to prevent imbalances in growth or losses of tissue integrity. A central goal of NHGRI's research is to learn how the human genome achieves these tasks and how disease states arise from DNA mutations and other obstacles to the deployment of genomic instructions.
Gastrulation is one the earliest steps of self-assembly. During gastrulation, three primary embryonic cell lineages are formed and the cells of two of these lineages — mesoderm and endoderm — undergo dramatic movements. This causes morphogenesis of the embryo's anatomy and establishes its basic body plan. Beyond gastrulation, descendants of mesoderm and endoderm cells will form most of the body's inner tissues, such as bones, blood and muscle from mesoderm, while the gut and vital organs are formed from endoderm.
Human embryos undergo gastrulation during the third week of pregnancy. Major aberrations in gastrulation cause early pregnancy loss. Moderate aberrations can have more devastating consequences, ranging from later-term miscarriage to stillbirth or severe birth defects. The gastrulation-related birth defect of the highest known incidence is holoprosencephaly, which arises from incomplete specification of mesoderm and endoderm and is estimated to occur in 1 in 250 embryos. A detailed understanding of the molecular and cellular mechanisms of gastrulation can pinpoint the causes of these and other birth defects. Indeed, basic research on gastrulation in vertebrate model organisms has already identified risk factors for human birth defects, and future research holds the promise of further progress.
Zebrafish are ideal for the study of gastrulation, since a single mating pair produces dozens to hundreds of embryos. Embryos develop outside of the mother, allowing non-invasive observation, and gastrulation is completed within twelve hours. In addition, powerful genetic and genomic tools are available for zebrafish research, and raising zebrafish is relatively cost-effective. Prior to joining NHGRI, Dr. Feldman studied zebrafish with mutations in genes encoding two members of the TGF beta superfamily: nodal-related 1 (ndr1, also called squint) and nodal-related 2 (ndr2, also called cyclops). Zebrafish with mutations in either of these genes develop holoprosencephaly, and Dr. Feldman showed that ndr1;ndr2 compound mutants lack all endoderm and most mesoderm. He also found that two Nodal antagonists, Lefty1 and Lefty2, are essential for limiting excess Ndr1 signaling and excess mesoderm and endoderm formation.
Dr. Feldman has continued his investigations into Nodal signaling while at NHGRI. His studies in this area have focused on Foxh1, a transcription factor that plays a key role in the Nodal signaling pathway. Dr. Feldman's laboratory has shown that maternal Foxh1 found in developing embryos controls production of certain keratin proteins that are essential for viable gastrulation. The role of Foxh1 in this process is distinct from its role in Nodal signaling. His laboratory has also identified a number of environmental factors, such as temperature, and genetic factors, such as the heat shock protein Hsp90, that influence the frequency of holoprosencephaly in zebrafish with a mutation in the ndr1 gene. This study demonstrates the power of using zebrafish as a model organism for understanding the complex origins of holoprosencephaly. In addition, and in line with NIH and NHGRI's mission in promoting translational research, Dr. Feldman has worked with colleagues in the Medical Genetics Branch to elucidate risk factors for human holoprosencephaly and pediatric cardiac laterality syndromes.
Dr. Feldman's principal research efforts have been devoted to applying high-throughput functional genomic strategies to fundamental questions of mesoderm and endoderm differentiation. His laboratory is searching for the upstream signals that induce Nodal signaling, as well as mesoderm and endoderm differentiation. They are also working to elucidate molecular cascades, particularly gene-regulatory networks of transcription factors, which guide mesoderm and endoderm differentiation after they are induced. Dr. Feldman and colleagues developed a flexible method for embryonic dissection; this method has been used to perform a genome-wide survey of the genes expressed in newly formed mesoderm and endoderm. His group performed an analogous examination of the genes expressed in the zebrafish embryo's yolk, which contains mesoderm and endoderm-inducing activities of unknown identity.
The Feldman lab's future work is dedicated to determining the functions of proteins encoded by mesodermal, endodermal and yolk genes. They are particularly interested in the roles of transcription factors that regulate mesoderm and endoderm precursor cells and of secreted proteins that are involved in signaling between the yolk and embryonic cells. This future work will be facilitated through the use of a novel high-throughput time-lapse documentation system they created. This system will be used to identify any developmental anomalies that arise in zebrafish embryos in which translation of signaling proteins or transcription factors has been blocked via introduction of antisense nucleic acid analogs.
Last Updated: September 18, 2009
