Lmo4a Deficiency Impairs Hearing And Balance Ability In Zebrafish

Deafness effects the health of human seriously. Hearing loss affects approximately27million in the china alone and has a high incidence-about278million people suffer from moderate to severe hearing loss in the world. It can be safely assumed that all children with congenital sensory hearing loss would have detectable abnormalities in their inner ears if they could be examined histologically. Development of therapies to treat hearing loss and balance disorders iscomplicated by the diversity of disease processes leading to functional loss and the current approaches available for treatment. Despite the significant impact of hearing and balance disorders on the general population there are currently no dedicated pharmaceuticals that target the inner ear.Incidence reduction, early detection, and early treatment of hearing loss have become a common interest of society. Prevention and treatment of Inner Ear Malformations and sensorineural deafness basic research is still hot and difficult.The role for LMO4, initially described as a human breast tumor autoantigen, in developing mammary epithelium and breast oncogenesis. In mouse, LMO4is initially expressed in the dorsolateral portion of the otic vesicle and its expression persists in the semicircular canals, macula, crista throughout embryogenesis indicating its important role in the mouse inner ear development. Targeted disruption of Lmo4resulted in the dysmorphogenesis of the vestibule and in the absence of three semicircular canals, anterior and posterior cristae.Zebrafish has two homologous genes Imo4a and Imo4b. Transcripts of both genes were present in unfertilized eggs, suggesting a maternal origin. Imo4a expression is rather dynamic, mainly in the developing mesoderm and neural plate at late gastrula and segmentation stages. The onset of Imo4a in the otic organs was detected weakly in the otic placode at14hpf. From then on, Imo4a is expressed outside the developing otic vesicle, as well as at anterior-dorsal tip and the ventral part of the vesicle. At24hpf, Imo4a expression likely includes some ventral cells of the vesicle and perhaps newly emerged hair cell precursors. At36hpf, Imo4a expression is seen in the anterior, ventra-lateral and posterior positions, perhaps marking the3developing cristae. The epithelial protrusions, which form the future semicircular canal system, start to undergo morphological change at48hpf, and weak Imo4a expression is detected in the apical protrusion.No obvious otic phenotype was detected in Imo4b morphants,so further research was focus on the function of Imo4a in the inner ear.Loss of Imo4a function leads to proportional reduction of otocyst size, hair cells statoacoustic ganglia. The markers that can highlight the preplacodal ectoderm (PPE. eyal and six4.1), or early sensory cells that derived from the PPE(i.e., ngnl, atoh1b and dlx3/4b) are down-regulated suggesting there is an overall decrease of gene expressions in the caudal PPE and PPE derived cells in the morphants and there is an early otic specification defect that leads to a general defect of inner ear functions.However, a failure to grow the semicircular canals (SSCs) in Imo4a morphants suggests us a direct link between Imo4a and SSC epithelial budding event.Because bmp4, bmp2b,which, are normally expressed in sequence at the epithelial protrusion buds of the otic vesicle, are all elevated in lmo4aMO ears, we reason that up-regulation of Bmp signaling may prevent the outgrowth of the protrusions in the morphants. As our presumption,injection AMP-activated protein kinase (AMPK) inhibitor(DM, Dorsomorphin) to the otic vesicle can partically rescue the semicircular canals phenotype.In summary, Imo4a in vivo may regulate Bmps, promoting semicircular morphogenesis. This is the first study exploring a significant opportunity for the development of local delivery of the small molecule DM as a totally new therapeutic approach for inner ear malformation and deafness.