title: Interplay of proliferation and proapoptotic and antiapoptotic factors is revealed in the early human inner ear development.
abstract: OBJECTIVE
  Spatiotemporal interplay of factors controlling proliferation, differentiation and apoptosis within the developing human inner ear is essential for labyrinth morphogenesis and development of vestibular and cochlear functions.
  
  
  BACKGROUND
  Studies on the early human inner ear development are scarce and insufficient.
  
  
  METHODS
  The immunolocalization of Ki-67, Bcl-2, caspase-3, and IGF-1 was analyzed in 6 human inner ears, 5 to 10 gestational weeks old. Statistical data were analyzed using the Kruskal-Wallis test.
  
  
  RESULTS
  During the analyzed period, the otocyst has transformed into cochlear duct and saccule ventrally and semicircular canals and utricle dorsally. Initial differentiation of sensorineural fields characterized organ of Corti, maculae, and cristae ampullares. Intense (50%) and evenly distributed proliferation Ki-67 in the otocyst decreased to 24% to 30% and became spatially restricted within the membranous labyrinth epithelium. Simultaneously, expression of antiapoptotic Bcl-2 protein increased in sensorineural fields of organ of Corti, macula, and crista ampullaris. Throughout the investigated period, apoptotic caspase-3 positive cells were mainly distributed at the luminal and basal surfaces of labyrinth epithelium. An inhibitor of apoptosis IGF-1 co-expressed with Bcl-2 and increased in the sensorineural fields with advancing development.
  
  
  CONCLUSIONS
  The described expression pattern indicates roles for cell proliferation in the growth of the inner ear and Bcl-2 in differentiation of sensorineural fields and protection from apoptosis. Both IGF-1-and caspase-3-mediated apoptosis seem to contribute to proper morphogenesis, differentiation, and innervations of sensorineural fields within the cochlea, semicircular canals, saccule, and utricle. Alterations in spatiotemporal interplay of investigated factors might lead to disturbances of vestibular and cochlear function.
authors.affiliation: *Department of Otorhinolaryngology, University Hospital in Split; †Department of Anatomy, Histology and Embryology, School of Medicine, University of Split, Split, Croatia; and ‡Department of Medical Neuroscience, Dalhousie University Faculty of Medicine, Halifax, Nova Scotia, Canada.
authors.forename: Robert
authors.initials: R
authors.lastname: Tafra
authors.forename: Snjezana Mardesic
authors.initials: SM
authors.lastname: Brakus
authors.forename: Katarina
authors.initials: K
authors.lastname: Vukojevic
authors.forename: Boris
authors.initials: B
authors.lastname: Kablar
authors.forename: Zavisa
authors.initials: Z
authors.lastname: Colovic
authors.forename: Mirna
authors.initials: M
authors.lastname: Saraga-Babic
mesh_terms: D000328:Adult; D051017:Apoptosis Regulatory Proteins / Q000502:physiology*; D053148:Caspase 3 / Q000378:metabolism; D049109:Cell Proliferation / Q000187:drug effects*; D003051:Cochlea / Q000196:embryology / Q000502:physiology; D007758:Ear, Inner / Q000196:embryology* / Q000378:metabolism / Q000502:physiology*; D005260:Female; D019084:Fluorescent Antibody Technique, Indirect; D005865:Gestational Age; D006801:Humans; D007150:Immunohistochemistry; D007334:Insulin-Like Growth Factor I / Q000378:metabolism; D019394:Ki-67 Antigen / Q000378:metabolism; D011247:Pregnancy; D019253:Proto-Oncogene Proteins c-bcl-2 / Q000378:metabolism; D014722:Vestibule, Labyrinth / Q000196:embryology / Q000502:physiology
chemical_list: D051017:Apoptosis Regulatory Proteins; D019394:Ki-67 Antigen; D019253:Proto-Oncogene Proteins c-bcl-2; D007334:Insulin-Like Growth Factor I; D053148:Caspase 3