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Fibroblast Growth Factor 14 Modulates the Neurogenesis of Granule Neurons in the Adult Dentate Gyrus

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Abstract

Adult neurogenesis, the production of mature neurons from progenitor cells in the adult mammalian brain, is linked to the etiology of neurodegenerative and psychiatric disorders. However, a thorough understanding of the molecular elements at the base of adult neurogenesis remains elusive. Here, we provide evidence for a previously undescribed function of fibroblast growth factor 14 (FGF14), a brain disease-associated factor that controls neuronal excitability and synaptic plasticity, in regulating adult neurogenesis in the dentate gyrus (DG). We found that FGF14 is dynamically expressed in restricted subtypes of sex determining region Y-box 2 (Sox2)-positive and doublecortin (DCX)-positive neural progenitors in the DG. Bromodeoxyuridine (BrdU) incorporation studies and confocal imaging revealed that genetic deletion of Fgf14 in Fgf14 −/− mice leads to a significant change in the proportion of proliferating and immature and mature newly born adult granule cells. This results in an increase in the late immature and early mature population of DCX and calretinin (CR)-positive neurons. Electrophysiological extracellular field recordings showed reduced minimal threshold response and impaired paired-pulse facilitation at the perforant path to DG inputs in Fgf14 −/− compared to Fgf14 +/+ mice, supporting disrupted synaptic connectivity as a correlative read-out to impaired neurogenesis. These new insights into the biology of FGF14 in neurogenesis shed light into the signaling pathways associated with disrupted functions in complex brain diseases.

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Acknowledgments

This work was supported by NIH Grant R01MH095995 (F.L.). M.A.A. and T.K.A. are sponsored by King Saud University, Saudi Arabia, PhD scholarship (M.A.A.), and PhD scholarship (T.K.A.). We would like to acknowledge Dr. Heather Lander for proof reading the manuscript.

Author Contributions

M.A.A. and T.K.A.: contributed to the design of the work, the acquisition, analysis, interpretation of the data, and wrote the manuscript. M.A.A. and T.K.A.: performed tissue cryosectioning, immunohistochemistry, confocal images, and image analysis. M.A.A.: prepared and perfused mouse tissue, performed BrdU treatment, supervised, and maintained the animal colony and the animal genotyping in the laboratory. F.S. and M.N.N.: conducted and analyzed electrophysiological experiments. F.L.: all experiments were performed in her laboratory, provided funding, resources, and intellectual support, contributed to editing the manuscript, and supervised data analysis, acquisition, and interpretation of the manuscript.

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    Authors and Affiliations

    1. Pharmacology and Toxicology Graduate Program, The University of Texas Medical Branch, Galveston, TX, USA

      Musaad A. Alshammari & Tahani K. Alshammari

    2. Graduate Studies Abroad Program, King Saud University, Riyadh, Saudi Arabia

      Musaad A. Alshammari & Tahani K. Alshammari

    3. Biophysics Graduate Program, Institute of Human Physiology, Università Cattolica, Rome, Italy

      Federico Scala

    4. Mitchell Center for Neurodegenerative Diseases, The University of Texas Medical Branch, Galveston, TX, USA

      Fernanda Laezza

    5. Center for Addiction Research, The University of Texas Medical Branch, Galveston, TX, USA

      Fernanda Laezza

    6. Center for Biomedical Engineering, The University of Texas Medical Branch, Galveston, TX, USA

      Fernanda Laezza

    7. Department of Pharmacology and Toxicology, The University of Texas Medical Branch, Medical Research Building 7.102B, 301 University Boulevard, Galveston, TX, 77555, USA

      Musaad A. Alshammari, Tahani K. Alshammari, Miroslav N. Nenov, Federico Scala & Fernanda Laezza

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    Musaad A. Alshammari and Tahani K. Alshammari contributed equally to this work.

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    Fig. S1

    Dynamics of FGF14 expression in distinct cell populations in the DG. A–D Representative immunostaining of FGF14 (gray/red), DCX (green), and Sox2 (blue). E Zoom of cells co-stained with different markers (Sox2+ DCX−, Sox2+ DCX+, and Sox2− DCX+). F–H Corresponding pixel intensity profiles of lines (yellow) illustrated in E. I–L Representative immunostaining of FGF14 (gray/red), DCX (green), and NeuN (blue). M Zoom of selected cells co-stained with different markers (DCX+ NeuN−, DCX+ NeuN+, and DCX− NeuN+). N–P Corresponding pixel intensity profiles of lines (yellow) illustrated in M. Data are derived from n = 2 mice per group, three to four sections per mouse. Scale bars represent 40 μm in D and L. (GIF 137 kb)

    High resolution image (TIF 9659 kb)

    Fig. S2

    Immunofluorescence staining of FGF14 in distinct cell subtypes in the DG. A Early progenitor population detected by triple labeling with anti-nestin (red), anti-Sox2 (blue), and anti-DCX (green). B Quantification of DCX+ Sox2+ cells (n = 3 mice per group, two to three sections per mouse). Data are mean ± SEM. Scale bars represent 50 μm in A. (GIF 101 kb)

    High resolution image (TIF 5129 kb)

    Fig. S3

    Changes in CR- and CB-positive cell number upon Fgf14 deletion. A–C Immature neurons in the DG are detected by immunolabeling with anti-calretinin antibodies from different manufacturing companies (Swant A and Santa Cruz C) (gray and red); mature neurons are labeled with anti-calbindin (green) in A and with anti-NeuN (green) in C. B, D Quantification of CR+ cells in Fgf14 +/+ and Fgf14 −/− mice; data derived from independent experiments (n = 3 mice per group, four sections per mouse; in B, ***P < 0.001; in D, *P < 0.05, Student’s t test). Data are means ± SEM. Scale bars represent 100 μm in A and C. (GIF 202 kb)

    High resolution image (TIF 10.377 kb)

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    Alshammari, M.A., Alshammari, T.K., Nenov, M.N. et al. Fibroblast Growth Factor 14 Modulates the Neurogenesis of Granule Neurons in the Adult Dentate Gyrus. Mol Neurobiol 53, 7254–7270 (2016). https://doi.org/10.1007/s12035-015-9568-5

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