title: Interplay of proliferation and differentiation factors is revealed in the early human eye development.
abstract: BACKGROUND
  Eye development is a consequence of numerous epithelial-to-mesenchymal interactions between the prospective lens ectoderm, outpocketings of the forebrain forming optic vesicles, and surrounding mesenchyme. How different cell types forming eye structures differentiate from their precursors, and which factors coordinate complex human eye development remains largely unknown. Proper differentiation of photoreceptors is of special interest because of their involvement in the appearance of degenerative retinal diseases.
  
  
  METHODS
  Here we analyze the spatiotemporal expression of neuronal markers nestin, protein gene product 9.5 (PGP9.5), and calcium binding protein (S100), proliferation marker (Ki-67), markers for cilia (alpha-tubulin), and cell stemness marker octamer-binding transcription factor 4 (Oct-4) in histological sections of 5-12 -week human eyes using immunohistochemical and immunofluorescence methods.
  
  
  RESULTS
  While during the investigated developmental period nestin shows strong expression in all mesenchymal derivatives, lens, optic stalk and inner neuroblastic layer, PGP9.5 and S100 expression characterizes only neural derivatives (optic nerve and neural retina). PGP9.5 is co-localized with nestin and S100 in the differentiating cells of the inner neuroblastic layer. Initially strong proliferation in all parts of the developing eye gradually ceases, especially in the outer neuroblastic layer. Proliferating Ki-67 positive cells co-localize with nestin in the retina, lens, and choroid. Strong Oct-4 and alpha-tubulin immunoreactivity in the retina and optic nerve gradually decreases, while they co-localize in outer neuroblastic and nerve fiber layers.
  
  
  CONCLUSIONS
  The described expression of investigated markers indicates their importance in eye growth and morphogenesis, while their spatially and temporally restricted pattern coincides with differentiation of initially immature cells into specific retinal cell lineages. Alterations in their spatiotemporal interplay might lead to disturbances of visual function.
authors.affiliation: Department of Ophthalmology, University Hospital Centre Split, Spinciceva 1, 21000, Split, Croatia.
authors.forename: Anita
authors.initials: A
authors.lastname: Matas
authors.affiliation: Laboratory for Early Human Development, Department of Anatomy, Histology and Embryology, School of Medicine, University of Split, Soltanska 2, 21000, Split, Croatia.
authors.forename: Natalija
authors.initials: N
authors.lastname: Filipovic
authors.affiliation: Department of Ophthalmology, University Hospital Centre Split, Spinciceva 1, 21000, Split, Croatia.
authors.forename: Ljubo
authors.initials: L
authors.lastname: Znaor
authors.affiliation: Laboratory for Early Human Development, Department of Anatomy, Histology and Embryology, School of Medicine, University of Split, Soltanska 2, 21000, Split, Croatia.
authors.forename: Snjezana
authors.initials: S
authors.lastname: Mardesic
authors.affiliation: Laboratory for Early Human Development, Department of Anatomy, Histology and Embryology, School of Medicine, University of Split, Soltanska 2, 21000, Split, Croatia.
authors.forename: Mirna
authors.initials: M
authors.lastname: Saraga-Babic
authors.affiliation: Laboratory for Early Human Development, Department of Anatomy, Histology and Embryology, School of Medicine, University of Split, Soltanska 2, 21000, Split, Croatia. kvukojev@gmail.com.
authors.forename: Katarina
authors.initials: K
authors.lastname: Vukojevic
mesh_terms: D015415:Biomarkers / Q000378:metabolism*; D002454:Cell Differentiation / Q000502:physiology*; D049109:Cell Proliferation / Q000502:physiology*; D005123:Eye / Q000196:embryology* / Q000378:metabolism; D005136:Eye Proteins / Q000378:metabolism*; D019084:Fluorescent Antibody Technique, Indirect; D005865:Gestational Age; D006801:Humans; D007231:Infant, Newborn; D019394:Ki-67 Antigen / Q000378:metabolism; D009024:Morphogenesis; D064231:Nestin / Q000378:metabolism; D050814:Octamer Transcription Factor-3 / Q000378:metabolism; D009418:S100 Proteins / Q000378:metabolism; D043222:Ubiquitin Thiolesterase / Q000378:metabolism
chemical_list: D015415:Biomarkers; D005136:Eye Proteins; D019394:Ki-67 Antigen; C577484:NES protein, human; D064231:Nestin; D050814:Octamer Transcription Factor-3; D009418:S100 Proteins; C482860:UCHL1 protein, human; D043222:Ubiquitin Thiolesterase
keywords: Alpha-tubulin; Eye development; Nestin; Oct-4; PGP9.5; S100