- ASSOCIATE PROFESSOR Genetics and Genomic Sciences
- ASSOCIATE PROFESSOR Developmental and Regenerative Biology
- Cellular Differentiation
- Developmental Biology
- Developmental Neurobiology
- Epithelial Cells
- Gene Expressions
- Gene Regulation
- Human Genetics and Genetic Disorders
- Inner Ear
- Knockout Mice
- Molecular Biology
- Protein Degradation
- Protein Phosphatases
- Stem Cells
- Transcription Factors
- Transcriptional Activation and Repression
- Transgenic Mice
2006-present, Associate Professor, Genetics And Genomic Sciences and Developmental and Regenerative Biology
2003-2006, Scientist, McLaughlin Research Institute
1999-2003, Research Scientist, McLaughlin Research Institute
1998-1999, Instructor, Harvard Medical School/Brigham & Women's Hospital
NIH Scientific Review Group UKGD
2000 - 2003
National Science Foundation
1999 - 2000
Recipient of 50th Anniversary Program for Scholars in Medicine Fellowship
Harvard Medical School
1997 - 2000
Individual National Research Service Award
National Eye Institute/NIH
Genetic control of inner ear neurosensory cell development and renal progenitors
Dr. Xu Dr. Xu’s research interest focuses on the roles of transcriptional factor and phosphatase EYA and its cofactor factors SIX and other cofactors during mammalian organogenesis. Mutations in these genes cause sensorineural hearing loss and renal diseases in humans. Work in the Xu laboratory involves mechanistic characterizations of these genes and their functions in the development and growth of vertebrate inner ear and kidney as well as in sensory neurogenesis.
Hearing loss is the most frequent sensory defect in humans and about one in 1,000 children is affected by severe deafness at birth or during early childhood. The primary cause is damage to the inner ear sensory hair cells and their associated spiral ganglion neurons. In mammals, cochlear hair cells and their associated neurons do not regenerate, resulting in irreversible deafness. Work in our laboratory has focused on understanding the molecular and developmental pathogenesis of congenital deafness and addressing several key questions of when and how a set of transcription factors act to mediate development of sensory and neuronal cells during early stages of inner ear development. We have taken a multidisciplinary approach to these problems, including the application of experimental embryology, molecular biology, biochemistry, and human and mouse genetics as well as gain- and loss-of-function approaches. Work from our laboratory has shown that these factors are critical regulators for activating specific developmental programs for hair cell fate induction, hair cell differentiation, neuronal fate induction as well as cell proliferation and survival in the inner ear. Interestingly, misexpression of Eya1/Six1 is able to convert cochlear nonsensory cells to hair cellss. In contrast, when Eya1/Six1 are misexpressed with inner ear neuron-specific components of the SWI/SNF chromatin remodeling complex, cochlear nonsensory cells are converted to spiral ganglion neurons instead of hair cells. Surprisingly, we found that coexpression of Eya1/Six1 with the chromatin-remodeling complex is sufficient to induce direct conversion of mouse fibroblast 3T3 cells toward a neuron-like fate. Given the desperate need for entirely new auditory repair strategies, these results stimulate further research into the development of new therapeutic strategies for auditory regeneration and repair.
We have also found that these genes have multiple functions at different developmental stages during neurogenesis and sensory hair cell differentiation and maturation in the inner ear. Due to technical advances and necessary tools generated in our laboratory, we now can begin to ask how such multiple functions (nuclear vs cytoplasmic) mediate their effect on neurosensory cell specificatiopn, proliferation, differentiation and functional maturation.
Similar lines of research are being performed in renal system.
Xu J, Wong EY, Cheng C, Li J, Sharkar MT, Xu CY, Chen B, Sun J, Jin D, Xu PX. Eya1 interacts with Six2 and Myc to regulate expansion of the nephron progenitor pool during nephrogenesis. Developmental Cell 2014 Nov; 31(4).
Yan J, Zhang L, Xu J, Sultana N, Hu J, Cai X, Li J, Xu PX, Cai CL. Smad4 regulates ureteral smooth muscle cell differentiation during mouse embryogenesis. PLoS One 2014 Aug; 9(8).
Xu J, Nie X, Cai X, Cai CL, Xu PX. Tbx18 is essential for normal development of vasculature network and glomerular mesangium in the mammalian kidney. Developmental Biology 2014 Jul; 391(1).
Bao S, Zhu L, Zhuang Q, Wang L, Xu PX, Itoh K, Holzman IR, Lin J. Distribution dynamics of recombinant Lactobacillus in the gastrointestinal tract of neonatal rats. PloS One 2013 Mar; 8(3).
Sun J, Karoulia Z, Wong EY, Ahmed M, Itoh K, Xu PX. The phosphatase-transcription activator EYA1 is targeted by anaphase-promoting complex/Cdh1 for degradation at M-to-G1 transition. Molecular and Cellular Biology 2013 Mar; 33(5).
Wong EY, Ahmed M, Xu PX. EYA1-SIX1 complex in neurosensory cell fate induction in the mammalian inner ear. Hearing Research 2013 Mar; 297.
Rinkevich Y, Mori T, Sahoo D, Xu PX, Bermingham JR, Weissman IL. Identification and prospective isolation of a mesothelial precursor lineage giving rise to smooth muscle cells and fibroblasts for mammalian internal organs, and their vasculature. Nature Cell Biology 2012 Dec; 14(12).
Ahmed M, Xu J, Xu PX. EYA1 and SIX1 drive the neuronal developmental program in cooperation with the SWI/SNF chromatin-remodeling complex and SOX2 in the mammalian inner ear. Development (Cambridge, England) 2012 Jun; 139(11).
Ahmed M, Wong EY, Sun J, Xu J, Wang F, Xu PX. Eya1-Six1 interaction is sufficient to induce hair cell fate in the cochlea by activating Atoh1 expression in cooperation with Sox2. Developmental Cell 2012 Feb; 22(2).
Xu PX. The EYA-SO/SIX complex in development and disease. Pediatric Nephrology 2013 Jun; 28(6).
Nie X, Xu J, El-Hashash A, Xu PX. Six1 regulates Grem1 expression in the metanephric mesenchyme to initiate branching morphogenesis. Developmental Biology 2011 Apr; 352(1).
Nie X, Sun J, Gordon RE, Cai CL, Xu PX. SIX1 acts synergistically with TBX18 in mediating ureteral smooth muscle formation. Development (Cambridge, England) 2010 Mar; 137(5).
Chen B, Kim EH, Xu PX. Initiation of olfactory placode development and neurogenesis is blocked in mice lacking both Six1 and Six4. Developmental Biology 2009 Feb; 326(1).
Zou D, Erickson C, Kim EH, Jin D, Fritzsch B, Xu PX. Eya1 gene dosage critically affects the development of sensory epithelia in the mammalian inner ear. Human Molecular Genetics 2008 Nov; 17(21).
Hoskins BE, Cramer CH, Silvius D, Zou D, Raymond RM, Orten DJ, Kimberling WJ, Smith RJ, Weil D, Petit C, Otto EA, Xu PX, Hildebrandt F. Transcription factor SIX5 is mutated in patients with branchio-oto-renal syndrome. American Journal of Human Genetics 2007 Apr; 80(4).
Grifone R, Demignon J, Giordani J, Niro C, Souil E, Bertin F, Laclef C, Xu PX, Maire P. Eya1 and Eya2 proteins are required for hypaxial somitic myogenesis in the mouse embryo. Developmental Biology 2007 Feb; 302(2).
Zou D, Silvius D, Rodrigo-Blomqvist S, Enerbäck S, Xu PX. Eya1 regulates the growth of otic epithelium and interacts with Pax2 during the development of all sensory areas in the inner ear. Developmental Biology 2006 Oct; 298(2).
Zou D, Silvius D, Davenport J, Grifone R, Maire P, Xu PX. Patterning of the third pharyngeal pouch into thymus/parathyroid by Six and Eya1. Developmental Biology 2006 May; 293(2).
Sajithlal G, Zou D, Silvius D, Xu PX. Eya 1 acts as a critical regulator for specifying the metanephric mesenchyme. Developmental Biology 2005 Aug; 284(2).
Zou D, Silvius D, Fritzsch B, Xu PX. Eya1 and Six1 are essential for early steps of sensory neurogenesis in mammalian cranial placodes. Development (Cambridge, England) 2004 Nov; 131(22).
Grifone R, Laclef C, Spitz F, Lopez S, Demignon J, Guidotti JE, Kawakami K, Xu PX, Kelly R, Petrof BJ, Daegelen D, Concordet JP, Maire P. Six1 and Eya1 expression can reprogram adult muscle from the slow-twitch phenotype into the fast-twitch phenotype. Molecular and Cellular Biology 2004 Jul; 24(14).
Ruf RG, Xu PX, Silvius D, Otto EA, Beekmann F, Muerb UT, Kumar S, Neuhaus TJ, Kemper MJ, Raymond RM, Brophy PD, Berkman J, Gattas M, Hyland V, Ruf EM, Schwartz C, Chang EH, Smith RJ, Stratakis CA, Weil D, Petit C, Hildebrandt F. SIX1 mutations cause branchio-oto-renal syndrome by disruption of EYA1-SIX1-DNA complexes. Proceedings of the National Academy of Sciences of the United States of America 2004 May; 101(21).
Zheng W, Huang L, Wei ZB, Silvius D, Tang B, Xu PX. The role of Six1 in mammalian auditory system development. Development (Cambridge, England) 2003 Sep; 130(17).
Xu PX, Zheng W, Huang L, Maire P, Laclef C, Silvius D. Six1 is required for the early organogenesis of mammalian kidney. Development (Cambridge, England) 2003 Jul; 130(14).
Xu PX, Zheng W, Laclef C, Maire P, Maas RL, Peters H, Xu X. Eya1 is required for the morphogenesis of mammalian thymus, parathyroid and thyroid. Development (Cambridge, England) 2002 Jul; 129(13).
Buller C, Xu X, Marquis V, Schwanke R, Xu PX. Molecular effects of Eya1 domain mutations causing organ defects in BOR syndrome. Human Molecular Genetics 2001 Nov; 10(24).
Xu X, Xu PX. A modified cryosection method for mouse testis tissue. Tissue & Cell 2001 Apr; 33(2).
Xu PX, Adams J, Peters H, Brown MC, Heaney S, Maas R. Eya1-deficient mice lack ears and kidneys and show abnormal apoptosis of organ primordia. Nature Genetics 1999 Sep; 23(1).
Xu PX, Zhang X, Heaney S, Yoon A, Michelson AM, Maas RL. Regulation of Pax6 expression is conserved between mice and flies. Development (Cambridge, England) 1999 Jan; 126(2).
Xu PX, Cheng J, Epstein JA, Maas RL. Mouse Eya genes are expressed during limb tendon development and encode a transcriptional activation function. Proceedings of the National Academy of Sciences of the United States of America 1997 Oct; 94(22).
Xu PX, Woo I, Her H, Beier DR, Maas RL. Mouse Eya homologues of the Drosophila eyes absent gene require Pax6 for expression in lens and nasal placode. Development (Cambridge, England) 1997 Jan; 124(1).
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Dr. Xu has not yet completed reporting of Industry relationships.
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