Pin-Xian Xu

Research

The research in Dr. Xu's laboratory is focused on identifying the genetic pathways that control the critical early steps of mammalian organ formation.  Mainly, the lab is studying the role of the transcription coactivator Eya and its interacting homeodomain protein Six during mammalian organogenesis.  Over the past several years, the team has generated knockout mice for these genes and used the mice to begin to order the actions of these genes into a regulatory pathway.  Dr. Xu's team has taken a multidisciplinary approach to this problem, including the application of experimental embryology, molecular biology, biochemistry, and human and mouse genetics.  Work from the laboratory has shown that these genes are critical regulators for activating specific developmental programs for multiple organ systems.

One major project in the lab is to elucidate the molecular and genetic pathway(s) controlled by Eya and Six genes in early mammalian inner ear morphogenesis. The vertebrate inner ear develops from the otic placode, a one-cell-thick epithelium via multiple inductive processes.  A large number of otic genes have been isolated recently, however, their precise functions are largely unknown and the molecular and genetic pathway(s) regulating the morphogenetic processes of inner ear development are not established.  Recently, it was found that the murine Eya1 gene is expressed during the development of the auditory system and mutations in the human EYA1 gene cause Branchio-Oto-Renal (BOR) syndrome, a congenital birth defect that accounts for as many as 2% of profoundly deaf children. However, despite the identification of the responsible gene for BOR syndrome, the developmental and molecular basis of auditory defects occurring in BOR syndrome and the identity of the steps at which Eya1 functions in early otic development are unclear.  In Eya1-/- mouse embryos, the inner ear development arrests at the otic vesicle stage, indicating that Eya1 is a key gene required for early otic morphogenesis.  Molecularly, it was found that the expression of Six1, which encodes a homeodomain protein, requires Eya1 function in early otic epithelium and their gene products physically interact in vitro.  Moreover, it was recently discovered that Six1 is also a key gene for inner ear development and that mutations in the SIX1 gene also cause BOR syndrome. To dissect the developmental and molecular pathogenesis of auditory system defects occurring in BOR syndrome, Dr. Xu's lab is currently establishing the developmental and molecular basis of inner ear defects associated with Eya1- and Six1-deficiency.  

Another major focus in the lab is to elucidate the molecular mechanisms controlling the formation of a functional metanephric mesenchyme during early kidney development by examining the role of the transcriptional coactivator Eya1, its interacting homeodomain protein Six1 and their cofactors. In addition to the inner ear and kidney, the team recently found that these genes are essential for early cranial sensory neurogenesis. In vertebrates, all peripheral sensory neurons derive either from precursors in placodes or from neural crest cells. Placodes are focal regions of thickened ectoderm in the vertebrate head, which give rise to both neuronal and non-neuronal structures (the lens of the eye and the anterior pituitary). The neurogenic placodes include the olfactory, otic, trigeminal, and epibranchial placodes.  Of these, only the olfactory and otic placodes give rise to neuronal and non-neuronal components, while the trigeminal and epibranchial placodes generate exclusively sensory neurons of the trigeminal and the distal geniculate, petrosal and nodose ganglia. At present, how the placodal ectodermal cells are induced to differentiate into neuronal cells and the molecular mechanisms that direct their development along this pathway are not well established. Dr. Xu'slaboratory is currently investigating the roles of Eya and Six genes in the development of ectoderm-derived neurons.