Chemical Senses Vol. 30 No. suppl 1 © Oxford University
Press 2005; all rights reserved
The Roles of Brain-derived Neurotrophic Factor in the Development of Nasal Chemoreceptor Neurons
Department of Anatomy, School of Health Sciences, Kyorin University, Hachioji, Tokyo 192-8508, Japan
Correspondence to be sent to: Shigeru Takami, e-mail: takamis{at}kyorin-u.ac.jp
Key words: BDNFmRNA, olfactory receptor neurons, rat, TrkB, vomeronasal receptor neurons
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Introduction |
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 Top Introduction Expression of BDNF in...Developmental study for BDNF...TrkB protein in the...Co-localization of BDNF and...Possible modes of BDNF...AcknowledgementsReferences |
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Brain-derived neurotrophic factor (BDNF) is one of the neurotrophins, and known to facilitate differentiation, growth and maturation of neurons. BDNF binds to the high-affinity receptor, tyrosine kinase receptor B (TrkB) to initiate signal transduction (Korsching, 1993
;
Lindsay et al., 1994).
Olfactory and vomeronasal receptor neurons (ORNs and VRNs, respectively) are
chemoreceptors located in the nasal cavity of most mammalian species (Graziadei, 1977). In the olfactory epithelium
(OE) lining the olfactory mucosa (OM), progenitor cells differentiate into immature and
mature ORNs; a single dendrite extending from the apical pole of each soma reaches the
surface of the OE to form a dendritic ending, and a single axon from the base of the soma
runs downward to pass through the basement membrane of the OE to reach the brain. Similar
bipolar neurons are also contained in the vomeronasal sensory epithelium (VSE) of the
vomeronasal organ (VNO), and designated as VRNs or vomeronasal sensory cells/neurons
(Graziadei, 1977;
Takami, 2002). Although several
neurotrophic factors including neurotrophins are thought to be involved in the
development, maturation, and regeneration of ORNs (Carter and Roskams, 2002;
Schwob, 2002), the functional roles of
BDNF remain to be understood. In the case of the VRNs, we were the first to report the
distribution of BDNF and TrkB at both domestic (Takami et al., 2001) and international (Takami and Nishiyama, 1997b) meetings. In this
paper, we present summary of our recent studies concerning BDNF and TrkB in the rat OM
and VNO. Our overall research goal is to clarify functional roles of BDNF in the
differentiation and maturation of ORNs and VRNs.
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Expression of BDNF in ORNs and VRNs |
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TopIntroductionExpression of BDNF in...Developmental study for BDNF...TrkB protein in the...Co-localization of BDNF and...Possible modes of BDNF...AcknowledgementsReferences |
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Using immunohistochemical methods, we demonstrated that ORNs and VRNs of rats (Sprague–Dawley strain) were BDNF-immunoreactive. Western blot analyses demonstrated that OM and VNO, as well as several brain regions, contained 27 kDa bands (Takami et al., 1997
, 1999).
Double- and triple-labeling fluorescence methods confirmed the co-localization of BDNF
and protein gene product 9.5 (PGP) in ORNs (Figure
1A,B). PGP was expressed in both
mature and immature ORNs and VRNs (Taniguchi
et al., 1993;
Takami et al., 1995).
Similar findings were obtained from the VSE; VRNs contained both BDNF and PGP (Takami et al., 2001).
|
In situ hybridization (ISH) methods in which anti-sense and sense probes to cRNA BDNF demonstrated that ORNs and VRNs at postnatal day 1 (P1) and at 6 weeks old (6W) contained BDNFmRNA. RT–PCR analyses confirmed that BDNF was expressed in the OM and VNO as well as in the olfactory bulbs, cerebrum, and cerebellum, but not in the liver (Takami et al., 2000
,
2001). |
Developmental study for BDNF expression in the OE and VSE |
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TopIntroductionExpression of BDNF in...Developmental study for BDNF...TrkB protein in the...Co-localization of BDNF and...Possible modes of BDNF...AcknowledgementsReferences |
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We identified and localized the protein and mRNA of BDNF in the OE and VSE at embryonic day 20 (E20), P1, P7, P14, P28, 6W and 10W; both ORNs and VRNs in all ages expressed BDNF (Figure 2). Furthermore, detailed analyses for the OE at 6W demonstrated that the OE in the septal region of the nasal cavity contained much lower amounts of BDNFmRNA, when compared to the OE in the laterally located turbinates (Hasegawa et al., 2002
;
Takami et al., 2002). The
biological significance of this regional difference remains to be understood.
|
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TrkB protein in the OM and VNO |
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TopIntroductionExpression of BDNF in...Developmental study for BDNF...TrkB protein in the...Co-localization of BDNF and...Possible modes of BDNF...AcknowledgementsReferences |
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Immunoreactivity for TrkB was reported to be present in ORNs, VRNs and their axon bundles in the lamina propria (Takami and Nishiyama, 1997a
,b;
Takami et al., 1997).
Furthermore, our quantitative analysis for the intensity of TrkB immunofluorescence in
ORNs suggests that immature ORNs contain larger amounts of TrkB protein when compared to
mature ORNs that are immunoreactive for olfactory marker protein (OMP;
Takami et al., 2004).
A post-embedding immunogold method demonstrated that gold particles were present on
the membranes of olfactory cilia as well as olfactory axons (Takami et al., 1998). Thus, it is likely that
ciliary and axonal membranes are the actual sites where the binding of BDNF and TrkB does
take place.
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Co-localization of BDNF and TrkB |
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TopIntroductionExpression of BDNF in...Developmental study for BDNF...TrkB protein in the...Co-localization of BDNF and...Possible modes of BDNF...AcknowledgementsReferences |
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Double- and triple-labeling fluorescence methods and a combined method of ISH and immunofluorescence microscopy demonstrated that subpopulations of BDNF-expressing ORNs and VRNs contained TrkB (Figure 1A–C). Further analysis for these subpopulations is underway in our laboratory.
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Possible modes of BDNF actions within ORNs and VRNs |
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TopIntroductionExpression of BDNF in...Developmental study for BDNF...TrkB protein in the...Co-localization of BDNF and...Possible modes of BDNF...AcknowledgementsReferences |
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Our resent studies in albino rats indicate that (i) BDNF is produced by ORNs and VRNs during pre- and post-natal development as well as in adult stages; (ii) autocrine and paracrine modes of BDNF exist in the OE and VSE; and (iii) TrkB protein is localized at least in the ciliary and axonal membranes of ORNs. These findings suggest that BDNF is an important factor for developing and maintaining ORNs and VRNs. It is likely that BDNF plays a crucial role in the growth of axons, dendrites, and cilia/microvilli of ORNs and VRNs.
Except for ORNs and VRNs, sustentacular cells within the OE and VSE were another source for BDNF (Figure 1B). However, TrkB immunoreactivity was not detected in sustentacular cells (Figure 1C), suggesting that BDNF secreted by them may have biological effects exclusively on ORNs and VRNs.
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Acknowledgements |
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TopIntroductionExpression of BDNF in...Developmental study for BDNF...TrkB protein in the...Co-localization of BDNF and...Possible modes of BDNF...AcknowledgementsReferences |
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We wish to thank Dr Ichiro Matsuoka, Hokkaido University, for providing BDNF cDNA probe and Dr Frank L. Margolis, University of Maryland, for providing anti-goat OMP antiserum. We thank Ms Erina Yamamoto and Yukari Ota for their technical assistance. This research was supported by Grant-in-aid for ‘Scientific frontier promotion’ program from the Ministry of the Education, Cultures, Sports, Science and Technology, Japan (MEOSSTJ), two research grants (to S.T.) from MEOSSTJ.
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