Pivotal roles of Fezf2 in differentiation of cone OFF bipolar cells and functional maturation of cone ON bipolar cells in retina

• Published in: Experimental eye research Vol. 171; pp. 142 - 154
• Main Authors: Suzuki-Kerr, Haruna, Iwagawa, Toshiro, Sagara, Hiroshi, Mizota, Atsushi, Suzuki, Yutaka, Watanabe, Sumiko
• Format: Journal Article
• Language: English
• Published: England Elsevier Ltd 01.06.2018
• Subjects: Animals; Biomarkers - metabolism; Bipolar cells; Cell Differentiation - physiology; DNA-Binding Proteins - physiology; Electroretinography; Fluorescent Antibody Technique, Indirect; Gene Expression Regulation, Developmental - physiology; In Situ Hybridization; Knockout mouse; Mice; Mice, Inbred C57BL; Mice, Inbred ICR; Mice, Knockout; Mice, Transgenic; Microscopy, Electron, Transmission; Nerve Tissue Proteins - physiology; Plasmids; Real-Time Polymerase Chain Reaction; Retina; Retina - embryology; Retina - growth & development; Retinal Bipolar Cells - cytology; Retinal Bipolar Cells - physiology; Retinal Cone Photoreceptor Cells - cytology; Retinal Cone Photoreceptor Cells - physiology; Sequence Analysis, RNA; Transcription factor; TRPM Cation Channels - metabolism; Retina; Transcription factor; Bipolar cells; Knockout mouse
• ISSN: 0014-4835; 1096-0007
• DOI: 10.1016/j.exer.2018.03.017

During development of the retina, common retinal progenitor cells give rise to six classes of neurons that subsequently further diversify into more than 55 subtypes of neuronal subtypes. Here, we have investigated the expression and function of Fezf2, Fez zinc finger family of protein, in the developing mouse retina. Expression of Fezf2 transcripts was strongly observed in the embryonic retinal progenitors at E14.5 and declined quickly in subsequent development of retina. Then, in postnatal stage at around day 8, Fezf2 was transiently expressed then declined again. Loss-of-function analysis using retinas from mice in which Fezf2 coding region was substituted with β-galactosidase showed that Fezf2 is expressed in a subset of cone OFF bipolar cells and required for their differentiation. Using electroretinogram, we found that Fezf2 knockout retina exhibited significantly reduced photopic b-wave, suggesting functional abnormality of cone ON bipolar cells. Furthermore, reduced expression of synaptic protein Trpm1 and structural alteration of ON bipolar cell invagination, both of which affected cone photoreceptor terminal synaptic activity, was identified by transmission electron microscopy and immunohistochemistry, respectively. Taken together, our results show that Fezf2 is indispensable in differentiation of bipolar precursors into cone OFF bipolar cells and in functional maturation of cone ON bipolar cells during development of mouse retina. These results contribute to our understanding of how diversity of neuronal subtypes and hence specificity of neuronal connections are established in the retina by intrinsic cues. •Fezf2 transcription factor is expressed in a subset of cone bipolar cells.•Fezf2 is essential of differentiation of OFF bipolar.•Structure alteration of ON bipolar was observed in Fezf2-KO retina.•Coupling of differentiation of cone OFF- and ON-bipolar is proposed.