Sean Ryder graduated from the University of New Hampshire in 1995 with a bachelor’s degree in biochemistry. He studied the mechanisms of RNA folding and catalysis in the Department of Molecular Biophysics and Biochemistry at Yale University, earning a Ph.D. in 2001. He performed post-doctoral research at The Scripps Research Institute, where he was awarded a Damon Runyon fellowship to study post-transcriptional regulation and RNP assembly. He joined the faculty of the University of Massachusetts Medical School in 2005. His current research focuses on the role of RNA-binding proteins in the regulation of gene expression during differentiation and development, with a focus on oligodendrocyte biology and early embryogenesis. His work couples quantitative methods, molecular genetics, and high throughput approaches to map regulatory networks. He received a Scholar Award from the Worcester Foundation for Biomedical Research in 2006, and a Basil O’Connor Award from the March of Dimes in 2008.
Post-transcriptional regulation of maternal mRNA in development.
A major theme that emerges from the study of embryogenesis is that post-transcriptional regulation of maternal mRNAs is crucial to patterning of the developing zygote. As oocytes ripen, the chromosomal content of the egg is locked in meiosis until the time of fertilization, precluding transcription of the mRNAs inherited by the new organism. Maternal transcripts are produced and reversibly silenced in the earlier stages of oogenesis, in some organisms requiring the support of “nurse” cells to provide mRNA to the maturing oocyte. Moreover, the embryos of most animals do not transcribe their DNA until the zygote has divided one or more times. In most cases, zygotic transcription does not begin until several cell divisions have occurred, after a number of patterning and cell fate specification events have taken place. Thus, activation of maternal transcripts by maternal regulatory factors provides the starting point for formation of the body plan.
We are mapping the post-transcriptional regulatory circuitry that guides axis formation and cell fate specification in the nematode Caenorhabditis elegans. We use a combination of biochemical, biophysical, and molecular genetic methods to define the nucleotide sequence specificity and RNA-target specificity of each RNA-binding protein required for patterning. Through this work, will generate a comprehensive list of cis-acting regulatory sites in maternal transcripts. This work will provide a map that will guide dissection of the post-transcriptional regulatory mechanisms that contribute to development.
Post-transcriptional regulation of myelin formation.
Myelin is required for function of the vertebrate nervous system. It has a stereotypical structure, consisting of spiraling layers of specialized plasma membrane, containing a defined set of phospholipids and proteins. Many of these proteins are vital for myelin formation or maintenance. While it has long been known that myelin enhances the propagation of saltatory electrical impulses along the length of the myelinated axon, more recent studies have revealed additional functions. Mice with mutations in myelin proteins suffer from axon degeneration, demonstrating that myelin is required to maintain axon integrity. Additionally, interactions between myelin proteins and developing axons inhibit neurite outgrowth and suppress developmental plasticity. Thus, myelin is required for proper connectivity during neural development and for electrical activity and maintenance of mature neurons.
In the central nervous system, myelin is formed by specialized glial cells termed oligodendrocytes. The highly polarized nature of oligodendrocytes, together with the requirement that they sense and respond accurately to their extracellular environment, necessitates the development of strategies to control gene expression at regions distal to the cell body. These strategies could influence how the cell decides where to migrate, when to stop dividing and differentiate, and which axons to myelinate. Changes in gene expression at the post-transcriptional or post-translational level allow the cell to respond rapidly and regionally, compared to transcriptional changes that require involvement of the nucleus. Accordingly, several RNA-binding proteins are expressed in cells of the oligodendrocyte lineage where they play regulatory roles in oligodendrocyte maturation or myelin formation. We are mapping the RNA regulatory circuitry that guides oligodendrocyte differentiation.
Screening for small molecule inhibitors of nematode development.
Early developmental phenomena are guided by the asymmetric regulation of maternally supplied proteins and transcripts. Protein expression from maternal mRNAs is governed by a suite of RNA-binding proteins packaged into the cytoplasm during oogenesis. These RNA-binding proteins control the stability, translation efficiency, and/or localization pattern of distinct transcripts by recognizing sequence elements in the 3’-untranslated region (UTR) of target mRNAs. Currently, few tools exist to study specific regulatory networks guided by RNA-binding proteins during early development. Importantly, standard genetic analyses are complicated by the maternal effect, pleiotropy, and embryonic lethality. In order to dissect the spatial and temporal aspects of post-transcriptional regulation as a function of developmental stage, a set of small molecules that modulate the RNA-binding activity of these maternal factors is needed. Towards this end, we have established fluorescence polarization (FP) assays to monitor the association of several nematode proteins with RNA in vitro. We are screening for small molecule inhibitors using both our on-site small molecule screening facility and in collaboration with the MLPCN of the NIH. If specific inhibitors of nematode embryogenesis can be identified, these could potentially form a new class of anti-helminthics useful in the treatment of parasitic nematode infections.
For more information, please see the Ryder lab website.