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Neuroscience; Neurology; Ophthalmology
733 N. Broadway
329 MRB (Miller Research Building)
Baltimore MD 21205
Control of Neuronal and Glial Specification and Function
The vertebrate central nervous system (CNS) is an amazingly complex structure composed of distinct subtypes of neurons and glia. To identify the molecular mechanisms that regulate cell specification in the CNS, we use the mouse retina and hypothalamus, both of which arise from the ventral embryonic forebrain. The relatively simple anatomy of the retina provides an excellent system to identify molecular mechanisms that regulate neuronal cell fate. The hypothalamus, which is a central regulator of behaviors ranging from sleep to feeding to reproduction, offers an opportunity to bring the power of developmental genetics to help unravel the neural circuitry controlling a huge range of experimentally tractable and medically important behaviors. In recent years, we have worked to map out the transcriptional regulatory networks controlling the developmental competence of retinal progenitor cells, photoreceptor specification and survival, as well how retinal glia are specified and help promote photoreceptor survival. In the hypothalamus, we have identified transcription factors that are essential for specification of neural circuitry controlling circadian rhythms and sleep. We also discovered that tanycytes of the hypothalamic median eminence are a diet-responsive neural progenitor cell population. Future work will investigate the function of novel candidate regulators of retinal and hypothalamic cell identity, the role of previously uncharacterized hypothalamic cell subtypes in regulating motivated behaviors, and the contribution of tanycyte-derived neurogenesis to the regulation of feeding and body weight.
Bedont JL, LeGates TA, Slat EA , Byerly MS, Wang H, Hu J, Rupp AC, Qian J, Wong GW, Herzog ED, Hattar S, and Blackshaw S. Lhx1 controls terminal differentiation and circadian function of the suprachiasmatic nucleus. Cell Reports, 2014 7:609-22.
Salvatierra J, Lee DA, Zibetti C, Duran-Moreno M, Yoo S, Newman EA, Wang H, Bedont JL, de Melo J, Miranda-Angulo AL, Gil-Perotin S, Garcia-Verdugo JM, and Blackshaw S. The LIM homeodomain factor Lhx2 is required for hypothalamic tanycyte specification and differentiation. J Neurosci, 2014 34:16809-20.
Lee DA, Yoo S, Pak T, Salvatierra J, Velarde E, Aja S, and Blackshaw S. Dietary and sex-specific factors regulate hypothalamic neurogenesis in young adult mice. Frontiers in Neuroscience, 2014 8:15.
Pak T, Yoo SY, Miranda-Angolo AM, Wang H, and Blackshaw S. Rax-CreERT2 knock-in mice: a tool for selective and conditional gene deletion in progenitors and radial glia of the retina and hypothalamus. PLoS ONE, 2014, 9:e90381.
Liu S, Lamaze A, Liu Q, Tabuchi M, Yang Y, Fowler M, Bharadwaj R, Zhang J, Bedont JL, Blackshaw S, Lloyd TE, Montell C, Sehgal A, Koh K, and Wu MN. WIDE AWAKE mediates the circadian timing of sleep onset. Neuron, 2014 82:151-6.
Byerly MS, Swanson R, Kwon K, Aja S, Moran TH, Wong GW and Blackshaw S. Hypothalamic Neuron-derived Neurotrophic Factor (NENF) interacts with BDNF and melanocortin signaling to modulate food intake. American Journal of Physiology, (2013) e-pub ahead of print.
Roy A, de Melo J, Chaturvedi D, Thein T, Cabrera-Socorro A, Meyer G, Blackshaw S. and Tole S. Lhx2 is necessary for the maintenance of optic identity and for the progression of optic morphogenesis. J Neurosci, (2013) 33:6877-8
Lee DA, Bedont JL, Pak T, Wang H, Song J, Miranda-Angulo A, Takiar V, Charubhumi V, Balordi F, Takebayashi H, Ford E, Fishell G, and Blackshaw S. Tanycytes of the Hypothalamic Median Eminence Form a Diet-Responsive Neurogenic Niche. Nat Neurosci (2012), 15:700-2 (Highlighted in Nature Neuroscience, May 2012 and Nature Cell Biology, October 2012).
De Melo J, Miki K, Rattner A, Smallwood P, Zibetti C, Hirokawa K, Monuki ES, Campochario P, and Blackshaw S. Injury-independent induction of reactive gliosis in retinal Muller glia by loss of function of the LIM homeodomain transcription factor Lhx2. Proc Natl Acad Sci USA (2012) 109:4657-62.
Jeong JS, Jiang L, Albino E, Marrero J, Rho HS, Hu S, Woodard C, Vera C, Bayron-Poueymirou D, Rivera-Pacheco ZA, Ramos L, Torres-Castro C, Bonaventura J, Boeke JD, Pino I, Eichinger DJ, Zhu H and Blackshaw S. A human proteome microarray-based pipeline for efficient production of monospecific monoclonal antibodies. Molecular Cellular Proteomics (2012) 6;O111.016253.
Rapicavoli NA, Poth EM, Zhu H and Blackshaw S. The long noncoding RNA Six3OS acts in trans to regulate retinal development by modulating Six3 activity. Neural Development (2011) 6:23
De Melo J, Peng G-H, Chen S and Blackshaw S. Sall3 controls retinal cone photoreceptor and horizontal cell development. Development (2011) 138:2325-36. PubMed Reference Blackshaw S, Scholpp S, Placzek M, Ingraham H, Simerly R, and Shimogori T. Molecular pathways controlling development of thalamus and hypothalamus: from neural specification to circuit formation. J Neurosci.(2010) 30:14925-30.
Shimogori T, Lee D A, 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. NatNeurosci (2010) 13:767-75. (Highlighted in Nature Neuroscience, June 2010 and Faculty of 1000).
Rapicavoli N, Poth E, and Blackshaw S. The long noncoding RNA RNCR2 directs mouse retinal cell specification. BMC Developmental Biology (2010) 10:49.
Onishi A, Peng GH, Chen S, Blackshaw S. Pias3-dependent SUMOylation controls mammalian cone photoreceptor differentiation. Nat Neurosci (2010) 13:1059-65.
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.
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*, and Zhu H*. Profiling the human protein-DNA interactome reveals ERK2 as a transcriptional repressor of interferon signaling. Cell (2009) 139:610-22. (Highlighted in Cell, October 2009 and Faculty of 1000. *indicates corresponding author).
Onishi A, Peng GH, Du CH, Alexis U, Chen S, and Blackshaw, S. Pias3 directs rod photoreceptor development via SUMOylation of Nr2e3. Neuron (2009) 61:234-46. (Highlighted in Neuron, January 2009 and Faculty of 1000).
Blackshaw S, Harpavat S, Trimarchi J, Cai L, Huang H, Kuo WP, Weber G, Lee K, Fraioli RE, Cho S-H, Yung R, Asch E, Wong, WH, and Cepko CL Genomic analysis of mouse retinal development. PLoS Biol. (2004) 2:E247.
Blackshaw S., Fraioli RE, Furukawa, T, and Cepko, CL Comprehensive analysis of photoreceptor gene expression and the identification of candidate retinal disease genes. Cell, (2001) 107:579-89. (Highlighted in Cell, November 2001 and Faculty of 1000).