Share
PrintBenjamin Feldman, Ph.D.
B.A. University of California at Berkeley, 1985
Ph.D. Columbia University, 1995
(301) 443-5556
(301) 496-7184 
6 Center Dr
Bethesda, MD 20892
Dr. Feldman utilizes genomic, molecular and developmental biology strategies to investigate the genetic basis of germ layer formation during early embryogenesis and how errors in this process cause common birth defects. He is pursuing this research in zebrafish, a vertebrate model organism whose embryos are amenable to a wide range of experimental interventions. Germ layer formation establishes the mesoderm, endoderm and ectoderm lineages during gastrulation and is evolutionarily conserved in animals ranging from flatworms to humans. Elucidating the genetic basis of germ layer formation is essential to understanding the human genome and to identifying the genetic risks for gastrulation-related birth defects and pregnancy loss. In vertebrates, normal mesoderm and endoderm (mesendoderm) formation requires the controlled production and delivery of Nodal-related ligands (Ndrs), members of the TGF beta superfamily. Prior to joining NHGRI Dr. Feldman contributed to this understanding through his analysis of zebrafish with mutations in two Nodal-related genes: ndr1, also called squint, and 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 anterior 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 congenital heart defects, and to develop a model for Costeff syndrome that he used to elucidate biochemical aspects of this infantile-onset metabolic disorder.
Dr. Feldman's principal research efforts have been devoted to elucidating the early embryonic mechanisms that initiate, complement and respond to signaling by Ndrs. As a starting point for these goals, Dr. Feldman and colleagues developed a flexible method for embryonic dissection that they used to identify genes expressed in newly formed mesoderm and endoderm and genes expressed in the zebrafish embryo's yolk, which contains mesoderm- and endoderm-inducing activities of unknown identity that act upstream of- and in parallel to Ndrs. The Feldman lab's future work is dedicated to determining the functions of proteins encoded by the genes they have identified in the mesoderm, endoderm and yolk. 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. They also plan to systematically analyze the expression and cross-regulation of the transcription factors expressed in the newly formed mesoderm and endoderm, with the goal of defining a comprehensive gene regulatory network underlying the specification of mesoderm and endoderm.
Last Reviewed: March 14, 2012
