Richard I. Dorsky, PhD
- Developmental Biology
- Gene Expression Regulation, Developmental
- Spinal Cord Injury
- Departments: Neurobiology & Anatomy - Professor
Academic Office Information
Biomedical Polymers Research Bldg
Neurobiology and Anatomy
20 S 2030 E, Room: 490 E
Salt Lake City, UT 84112
Spinal Cord Neurogenesis
We are interested in the functions of Wnt signaling and Tcf3 function in embryonic spinal cord development and regeneration. In addition to the roles of Wnt/Tcf-mediated transcription in spinal cord patterning and proliferation (Bonner, et al., Dev Biol, 2008), Tcf3 acts as a transcriptional repressor to prevent progenitor differentiation (Gribble et al., Development, 2009), indicating that it may function to maintain a stable population of multipotent progenitor cells.
One current project in the lab focuses on the cellular and molecular characterization of spinal progenitors following loss of Tcf3. We have generated tcf3 mutant zebrafish and are analyzing the phenotypes of spinal progenitors, and using gene expression analysis to identify Tcf3 targets. This work is testing the hypothesis that Tcf3 acts as a master regulator of the CNS progenitor state, similar to the known function for this protein in epidermal development.
A second project is investigating spinal progenitor response to injury. Zebrafish have a remarkable ability to fully regenerate their spinal cord following complete transection. We are using a transgenic approach to label spinal radial glia, and determining whether these cells undergo neurogenesis following injury, and if this response depends on Wnt/Tcf function.
This work focuses on the role of Wnt and Lef1 activity in post-embryonic neurogenesis. We previously identified a requirement for Lef1 in the formation of neural progenitors in the posterior hypothalamus (Lee et al., Development, 2006). This region of the brain maintains Wnt activity and continues to produce GABAergic neurons throughout life (Wang et al., Zebrafish, 2009), suggesting that Wnt-regulated neurogenesis plays an important role in the adult brain.
We are testing the hypothesis that post-embryonic hypothalamic neurogenesis regulated by Wnt signaling is important in feeding behavior. We are transgenically labeling newly-born GABAergic neurons to determine whether they integrate into feeding circuitry. We will also genetically manipulate these cells in vivo and test whether there are resulting behavioral effects. Evolutionary conservation of this cell population suggests that mammalian hypothalamic function may also be regulated by Wnt signaling.
To determine the functional role of Wnt signaling and Lef1 in the hypothalamus, we are using a conditional transgenic approach to modulate the pathway in vivo. These experiments will test whether Wnt signaling is required to promote neurogenesis in progenitor cells, regulating the rate of GABAergic neuron production. We are identifying Lef1 target genes in neural progenitors using whole-genome ChIP analysis and expression profiling in lef1 mutants.
|Postdoctoral Fellowship||University of Washington
|Doctoral Training||UC San Diego
- McPherson AD, Barrios JP, Luks-Morgan SJ, Manfredi JP, Bonkowsky JL, Douglass AD, Dorsky RI (2016). Motor Behavior Mediated by Continuously Generated Dopaminergic Neurons in the Zebrafish Hypothalamus Recovers after Cell Ablation. Curr Biol, 26(2), 263-9.
- Duncan RN, Xie Y, McPherson AD, Taibi AV, Bonkowsky JL, Douglass AD, Dorsky RI (2016). Hypothalamic radial glia function as self-renewing neural progenitors in the absence of Wnt/beta-catenin signaling. Development, 143(1), 45-53.
- May M, Hwang KS, Miles J, Williams C, Niranjan T, Kahler SG, Chiurazzi P, Steindl K, Van Der Spek PJ, Swagemakers S, Mueller J, Stefl S, Alexov E, Ryu JI, Choi JH, Kim HT, Tarpey P, Neri G, Holloway L, Skinner C, Stevenson RE, Dorsky RI, Wang T, Schwartz CE, Kim CH (2015). ZC4H2, an XLID gene, is required for the generation of a specific subset of CNS interneurons. Hum Mol Genet, 24(17), 4848-61.
- Briona LK, Poulain FE, Mosimann C, Dorsky RI (2015). Wnt/ss-catenin signaling is required for radial glial neurogenesis following spinal cord injury. Dev Biol, 403(1), 15-21.
- Otsuna H, Hutcheson DA, Duncan RN, McPherson AD, Scoresby AN, Gaynes BF, Tong Z, Fujimoto E, Kwan KM, Chien CB, Dorsky RI (2015). High-resolution analysis of central nervous system expression patterns in zebrafish Gal4 enhancer-trap lines. Dev Dyn, 244(6), 785-96.
- Duncan RN, Panahi S, Piotrowski T, Dorsky RI (2015). Identification of Wnt Genes Expressed in Neural Progenitor Zones during Zebrafish Brain Development. PLoS ONE, 10(12), e0145810.
- Briona LK, Dorsky RI (2014). Radial glial progenitors repair the zebrafish spinal cord following transection. Exp Neurol, 256, 81-92.
- Wehner D, Cizelsky W, Vasudevaro MD, Ozhan G, Haase C, Kagermeier-Schenk B, Roder A, Dorsky RI, Moro E, Argenton F, Kuhl M, Weidinger G (2014). Wnt/beta-catenin signaling defines organizing centers that orchestrate growth and differentiation of the regenerating zebrafish caudal fin. Cell Rep, 6(3), 467-81.
- Briona LK, Dorsky RI (2014). Spinal cord transection in the larval zebrafish.LID - 10.3791/51479 [doi]. J Vis Exp, (87).
- Nguyen TK, Tran VM, Sorna V, Eriksson I, Kojima A, Koketsu M, Loganathan D, Kjellen L, Dorsky RI, Chien CB, Kuberan B (2013). Dimerized glycosaminoglycan chains increase FGF signaling during zebrafish development. ACS Chem Biol, 8(5), 939-48.
- Kruse-Bend R, Rosenthal J, Quist TS, Veien ES, Fuhrmann S, Dorsky RI, Chien CB (2012). Extraocular ectoderm triggers dorsal retinal fate during optic vesicle evagination in zebrafish. Dev Biol, 371(1), 57-65.
- Wang X, Kopinke D, Lin J, McPherson AD, Duncan RN, Otsuna H, Moro E, Hoshijima K, Grunwald DJ, Argenton F, Chien CB, Murtaugh LC, Dorsky RI (2012). Wnt signaling regulates postembryonic hypothalamic progenitor differentiation. Dev Cell, 23(3), 624-36.
- Bonner J, Letko M, Nikolaus OB, Krug L, Cooper A, Chadwick B, Conklin P, Lim A, Chien CB, Dorsky RI (2012). Midline crossing is not required for subsequent pathfinding decisions in commissural neurons. Neural Dev, 7, 18.
- Kim HS, Dorsky RI (2011). Tcf7l1 is required for spinal cord progenitor maintenance. Dev Dyn, 240(10), 2256-64.
- Lin J, Wang X, Dorsky RI (2011). Progenitor expansion in apc mutants is mediated by Jak/Stat signaling. BMC Dev Biol, 11, 73.
- Gribble SL, Nikolaus OB, Carver MS, Hoshijima K, Dorsky RI (2009). Chromosomal position mediates spinal cord expression of a dbx1a enhancer. Dev Dyn, 238(11), 2929-35.
- Gribble SL, Kim HS, Bonner J, Wang X, Dorsky RI (2009). Tcf3 inhibits spinal cord neurogenesis by regulating sox4a expression. Development, 136(5), 781-9.
- Wang X, Lee JE, Dorsky RI (2009). Identification of Wnt-responsive cells in the zebrafish hypothalamus. Zebrafish, 6(1), 49-58.
- Veien ES, Rosenthal JS, Kruse-Bend RC, Chien CB, Dorsky RI (2008). Canonical Wnt signaling is required for the maintenance of dorsal retinal identity. Development, 135(24), 4101-11.
- Clark AM, Yun S, Veien ES, Wu YY, Chow RL, Dorsky RI, Levine EM (2008). Negative regulation of Vsx1 by its paralog Chx10/Vsx2 is conserved in the vertebrate retina. Brain Res, 1192, 99-113.
- Bonkowsky JL, Wang X, Fujimoto E, Lee JE, Chien CB, Dorsky RI (2008). Domain-specific regulation of foxP2 CNS expression by lef1. BMC Dev Biol, 8, 103.
- Bonner J, Gribble SL, Veien ES, Nikolaus OB, Weidinger G, Dorsky RI (2008). Proliferation and patterning are mediated independently in the dorsal spinal cord downstream of canonical Wnt signaling. Dev Biol, 313(1), 398-407.
- Gribble SL, Nikolaus OB, Dorsky RI (2007). Regulation and function of Dbx genes in the zebrafish spinal cord. Dev Dyn, 236(12), 3472-83.
- Lee JE, Wu SF, Goering LM, Dorsky RI (2006). Canonical Wnt signaling through Lef1 is required for hypothalamic neurogenesis. Development, 133(22), 4451-61.
- Veien ES, Grierson MJ, Saund RS, Dorsky RI (2005). Expression pattern of zebrafish tcf7 suggests unexplored domains of Wnt/beta-catenin activity. Dev Dyn, 233(1), 233-9.
- Dorsky RI, Itoh M, Moon RT, Chitnis A (2003). Two tcf3 genes cooperate to pattern the zebrafish brain. Development, 130(9), 1937-47.
- Dorsky RI, Sheldahl LC, Moon RT (2002). A transgenic Lef1/beta-catenin-dependent reporter is expressed in spatially restricted domains throughout zebrafish development. Dev Biol, 241(2), 229-37.
- Dorsky RI (2003). Transgenic reporters and modulators of Wnt/ beta-catenin signaling in the zebrafish CNS [Abstract]. American Association of Anatomists Annual Meeting.