|Department Affiliations||Neuroscience, Neurology and Ophthalmology|
|SOM Address||329 Miller Research Building|
My lab is interested in unraveling the mechanisms by which the amazingly diverse range of cell types of the central nervous system are specified during embryonic development. Defective development and survival of individual neuronal subtypes underlies a broad range of human diseases. Knowing precisely how these cells adopt their mature identities and what keeps them healthy once this process of differentiation is complete, may aid in design of therapies designed to correct these disorders. We focus on the development of the retina and hypothalamus, two structures that derive from the embryonic ventral forebrain. The retina is the starting point of all visual perception, while the hypothalamus is the central homeostatic regulator for a huge range of physiological processes, ranging from sleep to hunger to sexual behavior.
Using large-scale gene expression profiling as a starting point, we have identified hundreds of different genes in both structures which are excellent candidates for controlling cell specification during development, and have also developed state of the art proteomic tools which allow us to rapidly identify the biochemical targets of proteins and RNA molecules identified in this manner. Using this data, we have identified a network of transcription factors that are necessary and sufficient for development of retinal rod and cone photoreceptors, and other genes that are required for the development of retinal glia. Drugs that selective target one these proteins promote rod cell survival in models of hereditary photoreceptor dystrophy.
Furthermore, we have identified genes essential for development and function of the suprachiasmatic nucleus, the body’s master clock. We are also now using genetic tools to selectively manipulate the development and function identify the function of several previously uncharacterized hypothalamic neuronal subtypes, among which include cells whose activity is selectively regulated by food and sleep. Finally, we have identified a previously uncharacterized population of hypothalamic neural progenitor cells whose proliferation and differentiation is regulated by changes in diet. We are now working to determine the molecular cues regulating hypothalamic neurogenesis and the physiological consequences of interrupting this process.
- Hu S, Xie Z, Onishi A, Jiang L, Wang H, He X, Rho H-S, Woodard C, Yu X, Lin J, Long S, Blackshaw S*, Qian J*, Zhu H*. Profiling the Human Protein-DNA Interactome Reveals ERK2 as a Transcriptional Repressor of Interferon Signaling. Cell 2009 139:610-22 (*corresponding author).
- Onishi A, Peng GH, Du CH, Alexis U, Chen S, Blackshaw S. Pias3 directs rod photoreceptor development via SUMOylation of Nr2e3. Neuron 2009 61:234-46.
- Onishi A, Peng G-H, Chen J, Lee DA, Alexis, U, Poth E, de Melo J, Chen S, and Blackshaw S. The orphan nuclear hormone ERR regulates rod photoreceptor development and survival. Proc Natl Acad Sci USA 2010 107:11579-84.
- Onishi A, Peng GH, Chen S, Blackshaw S. Pias3-dependent SUMOylation controls mammalian cone photoreceptor differentiation. Nat Neurosci. 2010 13:1059-65.
- Shimogori T, Lee DA, Miranda-Angulo A, Yang Y, Yoshida A, Jiang L, Kataoka A, Wang H, Mashiko H, Avetisyan M A, Qi L, Qian J, and Blackshaw S. A genomic atlas of mouse hypothalamic development. Nat Neurosci. 2010 13:767-75
- The long noncoding RNA Six3OS acts in trans to regulate retinal development by modulating Six3 activity. Rapicavoli NA, Poth EM, Zhu H and Blackshaw S. Neural Development 2011 6:23