Research Description

1. Wnt and PCP signaling in mechanosensory hair cell polarity.
The actin-based hair bundle atop sensory hair cells is the mechanotransduction organelle essential for hearing and balance. A majority of sensorineural hearing loss (SNHL) disorders, including hereditary deafness, are caused by defects in the development or maintenance of the hair bundle. We investigate mechanisms underlying planar polarization of hair cells, which is crucial for the organization and orientation of the hair bundle. Our work in the last decade has provided fundamental new insights into a microtubule-based hair cell-intrinsic polarity machinery as well as intercellular Planar Cell Polarity (PCP) signaling for aligning hair cell orientation. Recently, we have uncovered a novel Wnt / heterotrimeric G protein / PI3K signaling pathway important for hair bundle morphogenesis This non-canonical Wnt signaling pathway coordinates cell-intrinsic and tissue-level PCP via multiple effectors, including PI3K, Rac1 and Gsk3b JCB 2020, Frontiers in Cell and Dev Biology, 2021). Current projects aim to elucidate the signal transduction machinery and downstream targets of the Wnt/G protein signaling pathway.
2. Innervation of auditory hair cells by spiral ganglion neurons.
Our sense of hearing is critically dependent on the spiral ganglion neurons (SGNs), which are biopolar afferent neurons that transmit sound information received by hair cells to the central nervous system. During development, SGNs establish highly stereotyped connections with hair cell targets in the auditory sensory epithelium. Multiple type I SGNs innervate each inner hair cells to transmit sound signals, while type II SGNs innervate multiple outer hair cells to detect acoustic trauma. Recent findings suggest that PCP signaling is involved in the guidance of type II SGN peripheral projections. We are interested in identifying the axon guidance cues generated by the cochlear epithelium and how they are regulated by PCP signaling. Loss of functional connections between SGNs and HCs underlie hearing impairments caused by both genetic and environmental factors. Therefore, understanding the developmental programs that establish the highly stereotyped wiring patterns in the cochlea is crucial for circuit repair and regeneration following damage.
3. PCP signaling and biomechanical regulation of neural tube closure.
We previously identified Ptk7, which encodes a receptor pseudokinase, as a key regulator of PCP and actomyosin contractility in multiple types of developing epithelia, such as the neural tube and the inner ear sensory epithelia. Ptk7 mutations have been identified in human patients with neural tube defects (NTD). However, how Ptk7 couples actomyosin contractility with the generation of planar polarity during neural tube morphogenesis is poorly understood. In collaboration with Dr. Ann Sutherland in the department, we leverage a CRISPR-generated Ptk7 allelic series carrying NTD patient variants and fluorescence imaging of cytoskeletal and Rho GTPase dynamics in intact live mouse embryos to understand biomechanical mechanisms crucial for neural tube morphogenesis.

Selected Publications

Landin Malt A., Clancy S., Hwang D., Liu A., Smith C., Smith M., Hatley M., Clemens C., Lu X., Non-Canonical Wnt Signaling Regulates Cochlear Outgrowth and Planar Cell Polarity via Gsk3beta Inhibition, 2021; Front Cell Dev Biol. 9() 649830. PMID: | PMCID: PMC8086559

Landin Malt A., Hogan A. K., Smith C. D., Madani M. S., Lu X., Wnts regulate planar cell polarity via heterotrimeric G protein and PI3K signaling, 2020; J Cell Biol. 219(10) . PMID: | PMCID: PMC7659710

Landin Malt A, Dailey Z, Holbrook-Rasmussen J, Zheng Y, Hogan A, Du Q, Lu X, Par3 is essential for the establishment of planar cell polarity of inner ear hair cells., 2019; Proceedings of the National Academy of Sciences of the United States of America. 116(11) 4999-5008. PMID: 30814219 | PMCID: PMC6421412

Tarchini B, Lu X, New insights into regulation and function of planar polarity in the inner ear., 2019; Neuroscience letters. 709() 134373. PMID: 31295539 | PMCID: PMC6732021

Goodyear RJ, Lu X, Deans MR, Richardson GP, A tectorin-based matrix and planar cell polarity genes are required for normal collagen-fibril orientation in the developing tectorial membrane., 2017; Development (Cambridge, England). 144(21) 3978-3989. PMID: 28935705 | PMCID: PMC5702074

Xu B, Washington AM, Domeniconi RF, Ferreira Souza AC, Lu X, Sutherland A, Hinton BT, Protein tyrosine kinase 7 is essential for tubular morphogenesis of the Wolffian duct., 2016; Developmental biology. 412(2) 219-33. PMID: 26944093 | PMCID: PMC4826835

Lu X, Sipe CW, Developmental regulation of planar cell polarity and hair-bundle morphogenesis in auditory hair cells: lessons from human and mouse genetics., 2015; Wiley interdisciplinary reviews. Developmental biology. 5(1) 85-101. PMID: 26265594 | PMCID: PMC4552040

Andreeva A, Lee J, Lohia M, Wu X, Macara IG, Lu X, PTK7-Src signaling at epithelial cell contacts mediates spatial organization of actomyosin and planar cell polarity., 2014; Developmental cell. 29(1) 20-33. PMID: 24703874 | PMCID: PMC4086913

Williams M, Yen W, Lu X, Sutherland A, Distinct apical and basolateral mechanisms drive planar cell polarity-dependent convergent extension of the mouse neural plate., 2014; Developmental cell. 29(1) 34-46. PMID: 24703875 | PMCID: PMC4120093

Sipe CW, Liu L, Lee J, Grimsley-Myers C, Lu X, Lis1 mediates planar polarity of auditory hair cells through regulation of microtubule organization., 2013; Development (Cambridge, England). 140(8) 1785-95. PMID: 23533177 | PMCID: PMC3621493

Lee J, Andreeva A, Sipe CW, Liu L, Cheng A, Lu X, PTK7 regulates myosin II activity to orient planar polarity in the mammalian auditory epithelium., 2012; Current biology : CB. 22(11) 956-66. PMID: 22560610 | PMCID: PMC3407606

Sipe CW, Lu X, Kif3a regulates planar polarization of auditory hair cells through both ciliary and non-ciliary mechanisms., 2011; Development (Cambridge, England). 138(16) 3441-9. PMID: 21752934 | PMCID: PMC3143564

Grimsley-Myers CM, Sipe CW, Wu DK, Lu X, Redundant functions of Rac GTPases in inner ear morphogenesis., 2011; Developmental biology. 362(2) 172-86. PMID: 22182523 | PMCID: PMC3267834

Paudyal A, Damrau C, Patterson VL, Ermakov A, Formstone C, Lalanne Z, Wells S, Lu X, Norris DP, Dean CH, Henderson DJ, Murdoch JN, The novel mouse mutant, chuzhoi, has disruption of Ptk7 protein and exhibits defects in neural tube, heart and lung development and abnormal planar cell polarity in the ear., 2010; BMC developmental biology. 10() 87. PMID: 20704721 | PMCID: PMC2930600

Grimsley-Myers CM, Sipe CW, Géléoc GS, Lu X, The small GTPase Rac1 regulates auditory hair cell morphogenesis., 2009; The Journal of neuroscience : the official journal of the Society for Neuroscience. 29(50) 15859-69. PMID: 20016102 | PMCID: PMC2847287

Yen WW, Williams M, Periasamy A, Conaway M, Burdsal C, Keller R, Lu X, Sutherland A, PTK7 is essential for polarized cell motility and convergent extension during mouse gastrulation., 2009; Development (Cambridge, England). 136(12) 2039-48. PMID: 19439496 | PMCID: PMC2685725