Elsevier

Neuroscience Research

Volume 66, Issue 1, January 2010, Pages 53-61
Neuroscience Research

Draxin, a repulsive axon guidance protein, is involved in hippocampal development

https://doi.org/10.1016/j.neures.2009.09.1710Get rights and content

Abstract

The hippocampus plays an essential role in learning and memory and is one of the major sites implicated in neural diseases. The proper organization of the hippocampus during development is important for its function. We found that draxin, a repulsive axon guidance cue, was widely expressed in the developing hippocampus and draxin deficient mice possessed a smaller hippocampus, particularly in the anterior part of the structure. Quantification of this reduction revealed that the volume of the dentate gyrus of the mutant was significantly smaller compared to the normal counterpart. This size reduction seemed to be dependent on apoptosis rather than due to a decrease in the rate of cell division.

Introduction

The hippocampus is an archicortical structure located at the caudomedial edge of the neocortex in mice (Amaral and Witter, 1995). The adult hippocampus forms an anatomically unique structure, with the longitudinal axis adopting a ‘C’ shape that is divided into distinct fields of the dentate gyrus (DG) and the CA1, CA2, and CA3 fields of Ammon's horn. This structure is one of the best-analyzed parts of the brain due to its involvement in the higher functions of learning and memory and in various neural diseases (Kandel, 2000). The hippocampus is absolutely necessary for making new memories and is affected severely and before other parts of the cortex in Alzheimer's disease. The hippocampus also seems to be involved in severe mental illnesses; it is reduced in size in both cases of schizophrenia and depression (Sapolsky, 2001). It is particularly vulnerable to ischemia, which selectively affects CA1 pyramidal neurons and destroys hippocampal circuitry by inducing cell death (Pulsinelli et al., 1982). Abnormal development of the hippocampus gives rise to pathological conditions involving cognitive dysfunction and seizures.

Many factors underlying the proper assembly of the hippocampus have already been identified, such as Wnt signaling pathway (Lee et al., 2000, Galceran et al., 2000, Zhou et al., 2004); the homeodomain protein Emx2 (Tole et al., 2000); fibroblast growth factor receptor 1 (Fgfr1) (Ohkubo et al., 2004); the proneural protein neurogenin 2 (Ngn2) (Galichet et al., 2008). Thus, various molecules such as growth and transcription factors are known to control the development of the hippocampus; however, such molecules as axon guidance proteins (Hinck, 2004) also have the potential to be involved in this development.

Draxin is a chemorepulsive axon guidance molecule required for development of the spinal cord and all forebrain commissures: the corpus callosum, hippocampal commissures and anterior commissures (Islam et al., 2009). Mouse draxin expression has been observed in many regions of the brain, including the hippocampus. In the present study, we examined the effects of draxin gene deprivation in hippocampal development. We found that draxin is widely expressed in the hippocampus by different cell types and that draxin knockout mice show abnormal hippocampal morphology and a loss of dentate granule cells.

Section snippets

Animal care and treatments

All experiments were carried out in accordance with the guidelines for the care and use of animals approved by the Animal Care and Use Committee (Kumamoto University). All efforts were made to minimize the number of animals used and their suffering. All of the mice used in this experiment were obtained either from a local company (wild type mice) or from a colony in an animal center in Kumamoto University (draxin knockout mice/β-galactosidase (β-gal) knockin and knockout mice). They were

Draxin is widely expressed in the developing hippocampus

To address the role of Draxin in development of the hippocampus, we first characterized the expression of draxin mRNA in the developing hippocampus of draxin/LacZ heterozygous mice. In situ hybridization and β-galactosidase staining was performed to detect expression from the draxin allele and revealed that draxin mRNA was widely expressed in the hippocampus, including the hippocampal ventricular zone (VZ), CA fields and the dentate gyrus at embryonic and early postnatal stages (Fig. 1A-D). The

Discussion

Formation of the hippocampal DG in mice begins at around E15 in the dorsomedial part of the telencephalic vesicles. The DG primordium is initially populated by Cajal–Retzius cells and radial glia that are likely to participate to its histogenesis (Rickmann et al., 1987, Del Rio et al., 1997, Alcantara et al., 1998, Borrell et al., 1999). The portion of the hippocampal neuroepithelium that constitutes the DG primordium, also called the primary matrix, contains stem/progenitor cells that give

Acknowledgements

We thank Dr. Kumimasa Ohta for comments on the manuscript. We thank the Developmental Studies Hybridoma Bank for antibodies. This work was supported by grants-in-aid from the Ministry of Education, Science, Sports and Culture of Japan, by the 21st Century COE Program and by the Global COE Program (Cell Fate Regulation Research and Education Unit), MEXT, Japan.

References (36)

  • M.J. Chumley et al.

    EphB receptors regulate stem/progenitor cell proliferation, migration, and polarity during hippocampal neurogenesis

    J. Neurosci.

    (2007)
  • J. Conover et al.

    Disruption of Eph/ephrin signaling affects migration and proliferation in the adult subventricular zone

    Nat. Neurosci.

    (2000)
  • J.A. Del Rio et al.

    A role for Cajal–Retzius cells and reelin in the development of hippocampal connections

    Nature

    (1997)
  • V. Depaepe et al.

    Ephrin signalling controls brain size by regulating apoptosis of neural progenitors

    Nature

    (2005)
  • C. Furne et al.

    Netrin-1 is a survival factor during commissural neuron navigation

    PNAS

    (2008)
  • J. Galceran et al.

    Hippocampus development and generation of dentate gyrus granule cells is regulated by LEF1

    Development

    (2000)
  • C. Galichet et al.

    Neurogenin 2 has an essential role in development of the dentate gyrus

    Development

    (2008)
  • M.S. Islam et al.

    Draxin, a repulsive axon guidance protein for spinal cord and forebrain commissures

    Science

    (2009)
  • Cited by (0)

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