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Ablation of TNAP function compromises myelination and synaptogenesis in the mouse brain

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Abstract

Mutations in the tissue-nonspecific alkaline phosphatase (TNAP) gene can result in skeletal and dental hypomineralization and severe neurological symptoms. TNAP is expressed in the synaptic cleft and the node of Ranvier in normal adults. Using TNAP knockout (KO) mice (Akp2-/-), we studied synaptogenesis and myelination with light- and electron microscopy during the early postnatal days. Ablation of TNAP function resulted in a significant decrease of the white matter of the spinal cord accompanied by ultrastructural evidence of cellular degradation around the paranodal regions and a decreased ratio and diameter of the myelinated axons. In the cerebral cortex, myelinated axons, while present in wild-type, were absent in the Akp2 -/- mice and these animals also displayed a significantly increased proportion of immature cortical synapses. The results suggest that TNAP deficiency could contribute to neurological symptoms related to myelin abnormalities and synaptic dysfunction, among which epilepsy, consistently present in the Akp2 -/- mice and observed in severe cases of hypophosphatasia.

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Acknowledgements

The authors acknowledge Dr Myriam Ermonval for fruitful discussion and Tünde Magyar, Magali Philippe and Luc Renaud for technical assistance. We thank Dr Etienne Mornet for his help in genotyping. This study was supported by PHC Egide (Balaton 17341UE), CNRS (PICS 4331), Hypophosphatasie Europe, University of Toulouse (ASUPS and ATUPS) (C.F), the French Embassy in Beijing (J.X), the joint funding by the National Office for Research and Technology (NKTH) and the Hungarian Science and Technology Foundation (TETALAP) (FR-16/2007) (L.N) and also supported in part by grant DE12889 from the National Institutes of Health, USA (J.L.M.).

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Authors and Affiliations

  1. Department of Anatomy, Histology and Embryology, Semmelweis University, Budapest, Hungary

    János Hanics & János Barna

  2. Centre de recherche Cerveau et Cognition (CerCo) UMR5549, CNRS and Université de Toulouse (UPS), Pavillon Baudot, CHU Purpan, BP 25202, 31052, Toulouse Cedex 3, France

    Jinsong Xiao & Caroline Fonta

  3. Zhongnan Hospital of Wuhan University, Hubei, People’s Republic of China

    Jinsong Xiao

  4. Sanford Children’s Health Research Center, Sanford-Burnham Medical Research Institute, La Jolla, CA, USA

    José Luis Millán

  5. Department of Theory, Institute for Particle and Nuclear Physics, Wigner Research Centre for Physics, Hungarian Academy of Sciences, P.O. Box 49, Budapest, 1525, Hungary

    László Négyessy

  6. Department of Anatomy, Histology and Embryology, Semmelweis University, Budapest, Hungary

    László Négyessy

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  1. János Hanics
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  2. János Barna
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  3. Jinsong Xiao
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  4. José Luis Millán
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  5. Caroline Fonta
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  6. László Négyessy
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Correspondence to Caroline Fonta or László Négyessy.

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János Hanics and János Barna equally contributed to data collection and analyses.

Caroline Fonta and László Négyessy equally contributed to all aspects of the study.

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Hanics, J., Barna, J., Xiao, J. et al. Ablation of TNAP function compromises myelination and synaptogenesis in the mouse brain. Cell Tissue Res 349, 459–471 (2012). https://doi.org/10.1007/s00441-012-1455-z

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