Developmental Genetics
The core question of developmental biology is how spatial organization of the body plan is achieved during embryogenesis such that a fertilized egg cell will give rise to a highly structured organism. Due to the identification and characterization of genes in several organisms and extensive progress in gene technology, many developmental processes are now being understood at the molecular level. One of the more important lessons from these studies is that homologous genes have related functions in invertebrates such as fruit flies and vertebrates such as the mouse. This insight implies that developmental processes will probably be best understood by integrating findings from several different organisms, each of which provides its own particular experimental advantages.
Scientists in the Developmental Genetics Program study a number of diverse developmental questions including: Establishment of the body axis by morphogen gradients, Regionalization of the embryonic xbrain into different structural and functional regions, Neural stem cell allocation and differentiation, Axon navigation and branching, Development of the embryonic eye, Heart development and analysis of heart function, Germ line development. Each research program integrates a genetic approach with the study of a variety of cellular processes like cell determination, cell lineage, and cell to cell signaling. A broad-organismal approach is provided through the use of a variety of experimental organisms, including Drosophila, chicken, mouse, rat and zebrafish.
Administrative Assistants:
Dolly Chan, Theresa Walton
During the development and maintenance of tissues and organs, cells must decide whether, when, where and how much to proliferate.
Improper control of cell proliferation can lead to developmental defects and cancer. We are focusing on the relatively unexplored area
of the control of pattern and extent of germline proliferation as a model for this process. In particular, we are interested in signaling
between somatic cells and the germ line that influences germline proliferation during development. Our entry into this area is aided by
our identification and analysis of C. elegans mutants that have germline tumors. We are using our detailed knowledge of germline tumor
formation to design and carry out large-scale genetic screens - including RNAi-based screens - to identify genes that affect tumor
formation. These approaches have identified candidate genes including genes involved in the insulin signaling pathway.
We have three general areas of interest in the lab. The first is pattern formation in the Drosophila eye disc. We have used
a genetic mosaic screen to identify novel genes required for the normal pattern of photoreceptor differentiation. Several of
these genes have given us insight into the mechanism of Hedgehog signaling and the role of the cytoskeleton in differentiation.
Secondly, we are interested in the interaction of signaling pathways with the general transcriptional machinery. We have evidence
that subunits of the mediator complex and the Brahma chromatin remodeling complex are specialized to transmit certain signals.
Finally, we are interested in axon guidance in the visual system, particularly in the mechanism by which the R7 photoreceptor
finds its correct target layer.
Embryonic development involves extensive cell and tissue movements. Cells are often born far from their final position and face the
challenge of navigating through the embryo to reach their destination and assemble into organs. To accomplish this task, they have
to correctly interpret guidance cues, interact with various tissues along their migratory route and communicate with each other.
We are trying to understand these principles using two different models: (1) The clustering of individual neuronal precursors into
a ganglion and (2) the migration of muscle and cartilage precursors into the head.
Early in the development of most organisms, primordial germ cells (PGCs) are set aside from those cells which form the organs
and tissues of the body. Although capable of giving rise to a new organism, germ cells are highly specialized. In many species,
germ cells form in a specialized cytoplasm that is synthesized during oogenesis and deposited in the egg. The location of this
specialized cytoplasm, containing key determinants for early development, determines where germ cells will form. Upon formation,
PGCs migrate on a distinct path through the developing embryo in order to reach a specific population of somatic cells where cellular
interactions essential for the differentiation of the gonad take place.
We are interested in the following aspects of germ cell development: 1) How is polarity established in the oocyte such that germ
plasm is only assembled at one egg pole? 2) What are the critical components of the germ plasm that make germ cells different from
somatic cells? 3) What guides germ cells during their migration in the embryo? We study these questions in Drosophila, where critical
molecules involved in any aspect of development can be efficiently identified using genetics.
During the morphogenetic movements of gastrulation, cells that will form
internal tissues become positioned within the interior of the developing embryo.
We use the nematode C. elegans as a model to understand some of the basic cellular
events that occur during gastrulation. C. elegans gastrulation involves the
ingression of cells into a small blastocoel cavity in the interior of the embryo.
We are interested in understanding 1) how the blastocoel cavity forms, 2) how ingression
movement occur, 3) how ingressions are triggered and patterned, and 4) how early embryonic
cells acquire an apicobasal polarity that is important for blastocoel formation
and ingression. C. elegans is ideally suited for such studies,
since individual cell movements can be followed in the optically clear embryo
and genes involved in gastrulation can be identified using genetics.
Agnel Sfeir joins the Developmental Genetics Program at the Skirball Institute of Biomolecular Medicine in January 2012. She obtained her PhD from UT Southwestern Medical Center in Dallas in 2006 and joined the lab of Titia de Lange at the Rockefeller University in New York. During her post-doctoral training, she combined cell biology and mouse genetics to understand the molecular pathways by which telomeres protect chromosome ends from the DNA damage response. At NYU Langone Medical Center, she is extending her studies in the telomere biology field, with an emphasis on telomere maintenance and function in stem cells.
Pluripotent stem cells have the unique capacity to differentiate into all adult cell types. At the same time, adult cells can be reprogrammed into pluripotent cells by experimental means such as the enforced expression of embryonic transcription factors. Using the mouse as the main model organism, we are investigating basic aspects of reprogramming and mammalian stem cell biology. These include the mechanisms that allow the establishment of pluripotency in differentiated cells and the molecular pathways that govern the differentiation of pluripotent stem cells into tissue-specific stem cells.
Dr. Mamta Tahiliani joins the Developmental Genetics and Molecular Pathogenesis Programs at the Skirball Institute and the Department of Biochemistry in January of 2011. During her graduate work with Anjana Rao, she studied the dynamic nature of covalent chromatin modifications. In collaboration with Yujiang Shi, she demonstrated that SMCX is a novel histone demethylase with a role in neuronal gene regulation. More recently, she discovered that the enzyme TET1 catalyzes the conversion of 5-methylcytosine (5mC) to 5-hydroxymethylcytosine (hmC) in mammalian DNA. She showed that hmC is present in the genome of mouse embryonic stem cells and that hmC levels decrease when embryonic stem cells differentiate.
The vertebrate vasculature displays a highly reproducable and pervasive anatomy, required for carrying its multiple vital functions.
Consequently, defective vessel growth contributes to the patogeneis of multiple human diseases. To understand the genetic pathways and
cellular strategies used by developing vessels to acquite their architecture, we are using genetic approaches and imaging tools to
study vascular development in zebrafish.
