Henry Ho, Ph.D.
Associate Professor
4421 Tupper Hall
Davis Campus

Wnt5a-Ror signaling in development and disease

How tissues and organs acquire their stereotypic shape during development is a fundamental but still poorly understood process. The overall goal of my research program is to understand how this process, generally known as tissue morphogenesis, is orchestrated at the molecular and cellular levels, and how defects in this process contribute to human disease. To this end, my laboratory has focused on an evolutionarily conserved and clinically relevant signaling pathway called the Wnt5a-Ror pathway. The Wnt5a-Ror pathway regulates tissue morphogenesis as well as other developmental and regenerative processes, and dysfunction of the pathway causes a broad range of human diseases, including structural birth defects, neurodevelopmental disorders and metastatic diseases. While rearrangements of the cytoskeleton are known to drive tissue morphogenesis, the mechanisms by which signaling pathways, such as the Wnt5a-Ror pathway, control cytoskeletal changes have been particularly difficult to decipher, because the downstream readouts of these pathways are non-transcriptional and cannot be easily detected using traditional transcription-based assays. My laboratory uses an intersectional approach of protein biochemistry and mouse genetics to uncover new components the Wnt5a-Ror pathway and develop novel tools for reading out pathway activity. It is our hope that by delineating the detailed mechanisms of Wnt5a-Ror signaling, we can better understand how this signaling pathway orchestrates organismal development and contributes to disease pathogenesis.

(an asterisk * denotes co-first or co-corresponding authors)

Wojcik MH, Okada K, Prabhu SP, Nowakowski DW, Ramsey K, Balak C, Rangasamy S, Brownstein CA, Schmitz-Abe K, Cohen JS, Fatemi A, Shi J, Grant EP, Narayanan V, Ho HH, Agrawal PB. De novo variant in KIF26B is associated with pontocerebellar hypoplasia with infantile spinal muscular atrophy. Am J Med Genet A. 2018 Aug 27. doi: 10.1002/ajmg.a.40493.

Karuna EP, Choi SS, Scales MK, Hum J, Cohen M, Fierro FA, Ho HH. Identification of a WNT5A-responsive degradation domain in the kinesin superfamily protein KIF26B. Genes, 9 (2018).

Karuna EP, Susman MW, Ho HH. Quantitative live-cell reporter assay for noncanonical Wnt activity. Bio-Protocol, 8 (2018).

Susman MW, Karuna EP, Kunz RC, Gujral TS, Cantú AV, Choi SS, Jong BY, Okada K, Scales MK, Hum J, Hu LS, Kirschner MW, Nishinakamura R, Yamada S, Laird DJ, Jao LE, Gygi SP, Greenberg ME, Ho HH. Kinesin superfamily protein Kif26b links Wnt5a-Ror signaling to the control of cell and tissue behaviors in vertebrates. eLife, 6 (2017).

Kamizaki K, Doi R, Hayashi M, Saji T, Kanagawa M, Toda T, Fukada SI, Ho HH, Greenberg ME, Endo M, Minami Y. The Ror1 receptor tyrosine kinase plays a critical role in regulating satellite cell proliferation during regeneration of injured muscle. The Journal of Biological Chemistry, 292(38):15939-15951 (2017).

Yuan J, Cha J, Deng W, Bartos A, Sun X, Ho HH, Borg JP, Yamaguchi TP, Yang Y, Dey SK. Planar cell polarity signaling in the uterus directs appropriate positioning of the crypt for embryo implantation. Proceedings of the National Academy of Sciences of the United States of America, 113(50):E8079-E8088 (2016).

O'Neill AK, Kindberg AA, Niethamer TK, Larson AR, Ho HH, Greenberg ME, Bush JO. Unidirectional Eph/ephrin signaling creates a cortical actomyosin differential to drive cell segregation. The Journal of Cell Biology, 215(2):217-229 (2016).

Arora R, Abby E, Ross AD, Cantu AV, Kissner MD, Castro V, Ho HY, Livera G, Laird DJ. Meiotic onset is reliant on spatial distribution but independent of germ cell number in the mouse ovary. Journal of Cell Science,129(13):2493-9 (2016).

Robichaux MA, Chenaux G, Ho HY, Soskis MJ, Greenberg ME, Henkemeyer M, Cowan CW. EphB1 and EphB2 intracellular domains regulate the formation of the corpus callosum and anterior commissure. Developmental Neurobiology, 76(4):405-20 (2016).

Hatakeyama J, Wald J, Printsev I, Ho HY, Carraway K: Vangl1 and Vangl2: planar cell polarity components with a developing role in cancer, Endocr Relat Cancer, Pii:ERC-14-0141 (2014).

Cha J, Bartos A, Park C, Sun X, Li Y, Cha SW, Ajima R, Ho HY, Yamaguchi TP, Dey SK. Appropriate crypt formation in the uterus for embryo homing and implantation requires Wnt5a-ROR Signaling. Cell Rep, 8(2): 382-92 (2014).

Robichaux MA, Chenaux G, Ho HY, Soskis MJ, Dravis C, Kwan KY, Šestan N, Greenberg ME, Henkemeyer M, Cowan CW. EphB receptor forward signaling regulates area-specific reciprocal thalamic and cortical axon pathfinding. Proc Natl Acad Sci USA, 111(6): 2188-93 (2014).

Ryu YK, Collins S, Ho HY, Zao H, Kuruvilla R. An autocrine Wnt5a-Ror signaling loop mediates sympathetic target innervation. Dev Biol, 377(1): 79-89 (2013).

Soskis MJ*, Ho HY*, Bloodgood BL, Robichaux MA, Malik A, Ataman B, Rubin AA, Zieg J, Zhang C, Shokat KM, Sharma N, Cowan CW, Greenberg ME. A chemical genetic approach reveals distinct mechanisms of EphB signaling during brain development. Nat Neurosci, 15(12): 1645-54 (2012).

Ho HY*, Susman MW*, Bikoff JB, Ryu YK, Jonas AM, Hu L, Kuruvilla R, Greenberg ME. Wnt5a-Ror-Dishevelled signaling constitutes a core developmental pathway that controls tissue morphogenesis. Proc Natl Acad Sci USA, 109(11): 4044-51 (2012).

Margolis SS, Salogiannis J, Lipton DM, Mandel-Brehm C, Wills ZP, Mardinly AR, Hu L, Greer PL, Bikoff JB, Ho HY, Soskis MJ, Sahin M, Greenberg ME. EphB mediated degradation of the RhoA GEF Ephexin5 relieves a developmental brake on excitatory synapse formation. Cell, 143(3): 442-55 (2010).

Ma YC, Song M, Park J, Ho HY, Kurtev M, Hu L, Pfaff S, Greenberg ME. Regulation of motor neuron identity establishment by GSK3-mediated phosphorylation of Neurogenin 2. Neuron, 58(1): 65-77 (2008).

Zhou Z, Hong EJ, Cohen S, Zhao WN, Ho HY, Schmidt L, Chen WG, Lin Y, Savner E, Griffith EC, Hu L, Steen JA, Weitz CJ, Greenberg ME. Brain-specific phosphorylation of MeCP2 regulates activity-dependent Bdnf transcription, dendritic growth, and spine maturation. Neuron, 52(2): 255-69 (2006).

Lebensohon AM, Ho HY, Ma L, Kirschner, MW. Cdc42 and PI(4,5)P2-induced actin assembly in Xenopus egg extracts, Methods in Enzymology, Vol. 406, pp. 156-73 (2006).

Ho HY, Lebensohon AM, Rohatgi R, Kirschner, MW. In vitro reconstitution of Cdc42-mediated actin assembly using purified components, Methods in Enzymology, Vol. 406, pp. 174-90 (2006).

Manchanda N, Lyubimova A, Ho HY, James MF, Gusella JF, Ramesh N, Snapper SB, Ramesh V. The NF2 tumor suppressor merlin and the ERM proteins interact with N-wasp and regulate its actin polymerization function. J Biol Chem, 280(13): 12517-22 (2005).

Ho HY*, Rohatgi R*, Lebensohn AM, Ma, L, Lee J, Gygi SP, Kirschner MW. Toca-1 mediates Cdc42-dependent actin nucleation by activating the N-WASP-WIP complex. Cell, 118(2): 203 (2004). #Faculty of 1000 “Must Read”.

Martinez-Quiles N, Ho HY, Kirschner MW, Ramesh N, Geha, RS. Erk/Src phosphorylation acts as a switch on-switch off mechanism that controls its ability to activate N-WASP. Molecular and Cellular Biology, 24(12): 5269 (2004).

Gautreau A, Ho HY, Li J, Steen H, Gygi SP, Kirschner MW. Purification and architecture of the ubiquitous Wave complex. Proc Natl Acad Sci USA, 101(13): 4379 (2004).

Rohatgi R, Nollau P, Ho HY, Kirschner MW, Mayer BJ. Nck and phosphatidylinositol 4,5-bisphosphate synergistically activate actin polymerization through the N-WASP-Arp2/3 pathway. J Biol Chem, 276(28): 26448-52 (2001).

Ho HY*, Rohatgi R*, Ma L, Kirschner MW. CR16 forms a complex with N-WASP in brain and is a novel member of a conserved proline-rich actin-binding protein family. Proc Natl Acad Sci USA, 98(20): 11306-11 (2001).

Rohatgi R*, Ho HY*, Kirschner MW. Mechanism of N-WASP activation by CDC42 and Phosphatidylinositol 4,5-bisphosphate. J Cell Biol, 150(6): 1299-310 (2000).

  • Damon Runyon Cancer Research Foundation Fellowship