Research The broad goal of my laboratory is to understand the mechanisms that underlie cell growth and differentiation. Cell communication is an important mechanism that involves the transduction of information from one cell to others via signaling molecules such as growth factors. One of the most versatile groups is the TGF-b family of signaling molecules. TGF-b molecules play crucial roles in directing cell growth and cell fate in diverse groups of organisms ranging from flies to humans. In humans they inhibit proliferation of lymphoid and hematopoietic cells thus limiting inflammatory response and promoting wound healing. They also induce bone morphogenesis in the developing fetus and adults. We use the fruit fly Drosophila melanogaster as a model system to identify and characterize the cellular responses to TGF-b signaling during development. The TGF-b molecule Dpp acts in a concentration dependent manner as a morphogen to subdivide the dorsal region of the fly embryo. High levels of Dpp are present in the dorsal most region of the developing embryo and instruct cells to differentiate into a flat squamous epithelial tissue called the amnioserosa. Lower levels of Dpp give rise to more lateral ectodermal cells that remain as columnar epithelia. We study the molecular mechanisms underlying Dpp morphogenetic activity. We recently demonstrated that the amnioserosa is established by a feed forward mechanism, whereby one regulator, Dpp, activates a second regulator, Zen, and then both regulate downstream target genes in the dorsal most region. We propose that Zen/Smads sit atop a genetic hierarchy comprising a set of direct target genes, as well as further downstream genes, that together function in a network that eventually leads to amnioserosa differentiation (Fig. 1). Our immediate goal is to identify the direct targets genes of Zen/Smads on a genome-wide scale by ChIP-on-chip. 
We further propose that some of the downstream genes in the network are regulators of cell division, cell shape changes, and cell polarity changes since these are all processes that are affected during the differentiation of squamous epithelial cells (flat like floor tiles) from the columnar (like bricks on end) morphology of the embryonic blastoderm. We are currently testing the roles of candidate genes involved in these processes such as cell cycle inhibitors, RhoGEFs and apical-basal polarity markers. A second project involves the transcription factor that appears to be responsible for activating the first set of zygotic genes in the early embryo. We called this factor, Zelda, for Zn-finger early Drosophila activator. It is present in the egg and begins to function by one hour after fertilization.
Without this activator, embryos do not make the transition from dependence on maternally-derived factors, which were placed into the egg during oogenesis, to dependence on their own genomes. Thus Zelda is a key regulator required for normal growth and development. Without Zelda, embryos do not develop normally and die by 3-4 hours. Many genes involved in cellular function, pattern formation, and sex determination are not activated in the absence of Zelda. We are currently examining how Zelda binds to enhancers of these genes to activate their transcription. Teaching I teach the undergraduate Genetics course. I participate in team-taught graduate lecture courses: Biocore I and II (the graduate core classes), and Developmental Genetics. I also run a graduate seminar, Current Topics in Genetics. In addition, I mentor several undergraduate students for their independent studies in the lab and their honors theses, as well as several Master's students for their Lab in Molecular Biology courses and Master's theses. Biosketch I received my Ph.D. from the University of Connecticut in 1983. My thesis mentor was Dr. Arthur Chovnick, a well known geneticist who studied gene organization in Drosophila. I moved to the laboratory of Dr. David Ish-Horowicz at the Imperial Cancer Research Fund in London, England to study developmental biology. I was particularly interested in the problem of cell fate determination. In 1986, I moved to Dr. Michael Levine's laboratory at Columbia University to study the problem of how morphogen gradients control cell fate. We discovered that the dorsal morphogen gradient is created by the mechanism of regulated nuclear transport. In 1991 I started my own lab at the Roche Institute of Molecular Biology in New Jersey where I showed how the dorsal morphogen acts as a transcriptional repressor to control target gene expression. In 1995 I joined the faculty of New York University as an associate professor and was tenured in 1999. We have been studying how Dpp functions as a morphogen and how it differs from the classical morphogens Dorsal and Bicoid. We showed that feed forward motifs predominate in how Dpp regulates downstream target genes rather than the differential binding affinity mechanism. Areas of Research/Interest Molecular mechanisms underlying early development in Drosophila External Affiliations Genetics Society of America, American Association for the Advancement of Science. Fellowships/Honors Whitehead Fellowship for Junior Faculty in Biological Sciences, 1996; American Cancer Society Research Grant NP600, July 1987-1991; American Cancer Society Postdoctoral Fellowship, November 1983-November 1985; PHS Genetics Training Grant, September 1978-September 1981.
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