Research InterestsDevelopmental Immunology, Innate Immunity
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Research in our laboratory is concerned with the gene expression programs that underlie animal immunity. We focus on the core gene regulatory networks that encompass transcription regulatory proteins, the DNA control sequences to which they bind, and their interconnections, along with the major signaling systems that convey nuclear states between cells. We are specifically interested in understanding regulatory networks that direct immunocyte specification and innate immune function. We employ the embryo and larva of the purple sea urchin (Strongylocentrotus purpuratus) as an uncomplicated experimental system in which to carry out these investigations. These animals offer advantages for this work including the availability of enormous quantities of staged embryos, highly efficient transgenesis, and the ability to specifically perturb the gene function using antisense and transgenic technologies. Importantly, sea urchins are echinoderms, a sister-group of the chordates, and they thus have a common genetic heritage with the vertebrates. The purple sea urchin genome sequence has now been resolved and this resource has revealed an innate immune system of unprecedented diversity that is rich with experimental opportunities to better understand our own immune system. Our research is anchored on the transcriptional regulatory networks that regulate aspects of mesodermal cell differentiation, particularly those that are likely to have homologous counterparts in vertebrate blood cell development and immunity. We approach these issues from two directions:
(1) We are characterizing expression of sea urchin homologs of regulatory factors that are well known as regulators of hematopoiesis and immunity in vertebrates. These are identified from the S. purpuratus genome sequence. Those that are coexpressed in the appropriate mesodermal cells form the core of a gene network in which we are analyzing regulatory interactions by perturbation and transcript measurements in the context of the intact embryo. Genes currently being characterized include homologs of vertebrate GATA-1/2/3, PU.1/Spi-B/Spi-C, E2A/HEB/ITF-2, SCL/Tal-2/Lyl-, and Id-1/2/3/4. All of these genes are important in the function of adult immune cells and in the development of larval immune cells.
(2) In a second approach, we are characterizing genes that are responsible for immune recognition, regulation and effector functions from the genome sequence and their expression in larvae. Genes in this category include those encoding toll-like receptors, Nod/Nalp-like proteins and SRCR domain proteins, genes that encode immune signaling molecules such as TNF family members and IL17 homologs, gene families with characteristics of antimicrobial peptides, and perforins. We are also looking at a variety of genes with homologs in the vertebrate adaptive immune system. Functional assays for bacterial clearance by larval cells have been developed and the roles of genes and gene network interactions will be tested in this context.
Ultimately this work will help clarify the relationship between programs of development and those that control terminal cell function. Work in this simple model reveals conserved gene regulatory circuitry that can then be characterized in more complicated vertebrate systems, but the sea urchin also provides an invaluable set of “natural experiments” that by comparison to humans illuminate the workings of our own immune system and give us access to entirely novel solutions to immune problems that are shared by all animals.
Publications and Awards
Rast JP, Smith LC, Loza-Coll M, Hibino T, Litman GW. 2006. Genomic insights into the immune system of the sea urchin. Science 314:952-6.
Sea Urchin Genome Sequencing Consortium. 2006. The genome of the sea urchin Strongylocentrotus purpuratus. Science. 314: 941-52.
Hibino T, Loza-Coll M, Messier C, Majeske AJ, Cohen AH, Terwilliger DP, Buckley KM, Brockton V, Nair SV, Berney K, Fugmann SD, Anderson MK, Pancer Z, Cameron RA, Smith LC, Rast JP. 2006. The immune gene repertoire encoded in the purple sea urchin genome. Dev Biol. 300:349-65.
Fugmann SD, Messier C, Novack LA, Cameron RA, Rast JP. 2006. An ancient evolutionary origin of the Rag1/2 gene locus. Proc Natl Acad Sci U S A. 103:3728-33.
Litman GW, Cannon JP, Rast JP. 2005. New insights into alternative mechanisms of immune receptor diversification. Adv Immunol. 87:209-36.
Calestani C, Rast JP, Davidson EH. 2003. Isolation of pigment cell specific genes in the sea urchin embryo by differential macroarray screening. Development 130: 4587-4596.
Rast JP, Cameron RA, Poustka AJ, Davidson EH. 2002. Brachyury target genes in the early sea urchin embryo isolated by differential macroarray screening. Dev. Biol. 246:191-208.
Davidson EH, Rast JP, Oliveri P, Ransick A, Calestani C, Yuh CH, Minokawa T, Amore G, Hinman V, Arenas-Mena C, Otim O, Brown CT, Livi CB, Lee PY, Revilla R, Rust AG, Pan Z, Schilstra MJ, Clarke PJ,
Arnone MI, Rowen L, Cameron RA, McClay DR, Hood L, Bolouri H. 2002. A genomic regulatory network for development. Science 295:1669-78.
Rast JP, Amore G, Calestani C, Livi CB, Ransick A, Davidson EH. 2000. Recovery of developmentally defined gene sets from high-density cDNA macroarrays. Dev Biol 228:270-86.
Rast JP, Anderson MK, Strong SJ, Litman RT, Litman GW. 1997. α, β, γ, and δ T cell antigen receptor genes arose early in vertebrate phylogeny. Immunity 6:1-11.