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7 Publications

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    Sternson Lab
    06/10/09 | Leptin targets in the mouse brain.
    Scott MM, Lachey JL, Sternson SM, Lee CE, Elias CF, Friedman JM, Elmquist JK
    The Journal of Comparative Neurology. 2009 Jun 10;514:518-32. doi: 10.1002/cne.22025

    The central actions of leptin are essential for homeostatic control of adipose tissue mass, glucose metabolism, and many autonomic and neuroendocrine systems. In the brain, leptin acts on numerous different cell types via the long-form leptin receptor (LepRb) to elicit its effects. The precise identification of leptin’s cellular targets is fundamental to understanding the mechanism of its pleiotropic central actions. We have systematically characterized LepRb distribution in the mouse brain using in situ hybridization in wildtype mice as well as by EYFP immunoreactivity in a novel LepRb-IRES-Cre EYFP reporter mouse line showing high levels of LepRb mRNA/EYFP coexpression. We found substantial LepRb mRNA and EYFP expression in hypothalamic and extrahypothalamic sites described before, including the dorsomedial nucleus of the hypothalamus, ventral premammillary nucleus, ventral tegmental area, parabrachial nucleus, and the dorsal vagal complex. Expression in insular cortex, lateral septal nucleus, medial preoptic area, rostral linear nucleus, and in the Edinger-Westphal nucleus was also observed and had been previously unreported. The LepRb-IRES-Cre reporter line was used to chemically characterize a population of leptin receptor-expressing neurons in the midbrain. Tyrosine hydroxylase and Cre reporter were found to be coexpressed in the ventral tegmental area and in other midbrain dopaminergic neurons. Lastly, the LepRb-IRES-Cre reporter line was used to map the extent of peripheral leptin sensing by central nervous system (CNS) LepRb neurons. Thus, we provide data supporting the use of the LepRb-IRES-Cre line for the assessment of the anatomic and functional characteristics of neurons expressing leptin receptor.

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    Sternson Lab
    10/01/05 | Topographic mapping of VMH –> arcuate nucleus microcircuits and their reorganization by fasting.
    Sternson SM, Shepherd GM, Friedman JM
    Nature Neuroscience. 2005 Oct;8(10):1356-63. doi: 10.1038/nn1550

    In the hypothalamic arcuate nucleus (ARC), pro-opiomelanocortin (POMC) neurons inhibit feeding and neuropeptide-Y (NPY) neurons stimulate feeding. We tested whether neurons in the ventromedial hypothalamic nucleus (VMH), a known satiety center, activate anorexigenic neuronal pathways in the ARC by projecting either excitatory synaptic inputs to POMC neurons and/or inhibitory inputs to NPY neurons. Using laser scanning photostimulation in brain slices from transgenic mice, we found that POMC and NPY neurons, which are interspersed in the ARC, are nevertheless regulated by anatomically distinct synaptic inputs. POMC neurons received strong excitatory input from the medial VMH (mVMH), whereas NPY neurons did not and, instead, received weak inhibitory input only from within the ARC. The strength of the excitatory input from the mVMH to POMC neurons was diminished by fasting. These data identify a new molecularly defined circuit that is dynamically regulated by nutritional state in a manner consistent with the known role of the VMH as a satiety center.

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    Sternson Lab
    09/01/04 | Modular synthesis and preliminary biological evaluation of stereochemically diverse 1,3-dioxanes.
    Wong JC, Sternson SM, Louca JB, Hong R, Schreiber SL
    Chemistry & Biology. 2004 Sep;11(9):1279-91. doi: 10.1016/j.chembiol.2004.07.012

    Modular synthesis and substrate stereocontrol were combined to furnish 18,000 diverse 1,3-dioxanes whose distribution in chemical space rivals that of a reference set of over 2,000 bioactive small molecules. Library quality was assessed at key synthetic stages, culminating in a detailed postsynthesis analysis of purity, yield, and structural characterizability, and the resynthesis of library subsets that did not meet quality standards. The importance of this analysis-resynthesis process is highlighted by the discovery of new biological probes through organismal and protein binding assays, and by determination of the building block and stereochemical basis for their bioactivity. This evaluation of a portion of the 1,3-dioxane library suggests that many additional probes for chemical genetics will be identified as the entire library becomes biologically annotated.

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    Sternson Lab
    04/11/02 | Dissecting glucose signalling with diversity-oriented synthesis and small-molecule microarrays.
    Kuruvilla FG, Shamji AF, Sternson SM, Hergenrother PJ, Schreiber SL
    Nature. 2002 Apr 11;416(6881):653-7. doi: 10.1038/416653a

    Small molecules that alter protein function provide a means to modulate biological networks with temporal resolution. Here we demonstrate a potentially general and scalable method of identifying such molecules by application to a particular protein, Ure2p, which represses the transcription factors Gln3p and Nil1p. By probing a high-density microarray of small molecules generated by diversity-oriented synthesis with fluorescently labelled Ure2p, we performed 3,780 protein-binding assays in parallel and identified several compounds that bind Ure2p. One compound, which we call uretupamine, specifically activates a glucose-sensitive transcriptional pathway downstream of Ure2p. Whole-genome transcription profiling and chemical epistasis demonstrate the remarkable Ure2p specificity of uretupamine and its ability to modulate the glucose-sensitive subset of genes downstream of Ure2p. These results demonstrate that diversity-oriented synthesis and small-molecule microarrays can be used to identify small molecules that bind to a protein of interest, and that these small molecules can regulate specific functions of the protein.

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    Sternson Lab
    12/27/01 | Synthesis of 7200 small molecules based on a substructural analysis of the histone deacetylase inhibitors trichostatin and trapoxin.
    Sternson SM, Wong JC, Grozinger CM, Schreiber SL
    Organic Letters. 2001 Dec 27;3(26):4239-42

    Seventy-two hundred potential inhibitors of the histone deacetylase (HDAC) enzyme family, based on a 1,3-dioxane diversity structure, were synthesized on polystyrene macrobeads. The compounds were arrayed for biological assays in a "one bead-one stock solution" format. Metal-chelating functional groups were used to direct the 1,3-dioxanes to HDAC enzymes, which are zinc hydrolases. Representative structures from this library were tested for inhibitory activity and the 1,3-dioxane structure was shown to be compatible with HDAC inhibition. [structure: see text]

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    Sternson Lab
    02/28/01 | Split--pool synthesis of 1,3-dioxanes leading to arrayed stock solutions of single compounds sufficient for multiple phenotypic and protein-binding assays.
    Sternson SM, Louca JB, Wong JC, Schreiber SL
    Journal of the American Chemical Society. 2001 Feb 28;123(8):1740-7

    Diversity-oriented organic synthesis offers the promise of advancing chemical genetics, where small molecules are used to explore biology. While the split--pool synthetic method is theoretically the most effective approach for the production of large collections of small molecules, it has not been widely adopted due to numerous technical and analytical hurdles. We have developed a split--pool synthesis leading to an array of stock solutions of single 1,3-dioxanes. The quantities of compounds are sufficient for hundreds of phenotypic and protein-binding assays. The average concentration of these stock solutions derived from a single synthesis bead was determined to be 5.4 mM in 5 microL of DMSO. A mass spectrometric strategy to identify the structure of molecules from a split--pool synthesis was shown to be highly accurate. Individual members of the 1,3-dioxane library have activity in a variety of phenotypic and protein-binding assays. The procedure developed in this study allows many assays to be performed with compounds derived from individual synthesis beads. The synthetic compounds identified in these assays should serve as useful probes of cellular and organismal processes.

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    Sternson Lab
    10/08/98 | An acid- and base-stable o-nitrobenzyl photolabile linker for solid phase organic synthesis.
    Sternson SM, Schreiber SL
    Tetrahedron Letters. 1998 Oct 8;39:7451-54

    The synthesis of an o-nitrobenzyl photolabile linker (1) from o-nitrobenzaldehyde is described, and the efficiency of its light-mediated (365 nm) cleavage is found to be comparable to related, previously developed systems. In contrast, 1 is shown to be stable to acid, base, and Lewis acid/amine combinations while the previously developed linker 2 is shown to degrade under the latter two conditions.

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