PMID- 22558255
OWN - NLM
STAT- MEDLINE
DCOM- 20120913
LR  - 20231213
IS  - 1932-6203 (Electronic)
IS  - 1932-6203 (Linking)
VI  - 7
IP  - 4
DP  - 2012
TI  - ProBDNF collapses neurite outgrowth of primary neurons by activating RhoA.
PG  - e35883
LID - 10.1371/journal.pone.0035883 [doi]
LID - e35883
AB  - BACKGROUND: Neurons extend their dendrites and axons to build functional neural 
      circuits, which are regulated by both positive and negative signals during 
      development. Brain-derived neurotrophic factor (BDNF) is a positive regulator for 
      neurite outgrowth and neuronal survival but the functions of its precursor 
      (proBDNF) are less characterized. METHODOLOGY/PRINCIPAL FINDINGS: Here we show 
      that proBDNF collapses neurite outgrowth in murine dorsal root ganglion (DRG) 
      neurons and cortical neurons by activating RhoA via the p75 neurotrophin receptor 
      (p75NTR). We demonstrated that the receptor proteins for proBDNF, p75NTR and 
      sortilin, were highly expressed in cultured DRG or cortical neurons. ProBDNF 
      caused a dramatic neurite collapse in a dose-dependent manner and this effect was 
      about 500 fold more potent than myelin-associated glycoprotein. Neutralization of 
      endogenous proBDNF by using antibodies enhanced neurite outgrowth in vitro and in 
      vivo, but this effect was lost in p75NTR(-/-) mice. The neurite outgrowth of 
      cortical neurons from p75NTR deficient (p75NTR(-/-)) mice was insensitive to 
      proBDNF. There was a time-dependent reduction of length and number of filopodia 
      in response to proBDNF which was accompanied with a polarized RhoA activation in 
      growth cones. Moreover, proBDNF treatment of cortical neurons resulted in a 
      time-dependent activation of RhoA but not Cdc42 and the effect was absent in 
      p75NTR(-/-) neurons. Rho kinase (ROCK) and the collapsin response mediator 
      protein-2 (CRMP-2) were also involved in the proBDNF action. CONCLUSIONS: proBDNF 
      has an opposing role in neurite outgrowth to that of mature BDNF. Our 
      observations suggest that proBDNF collapses neurites outgrowth and filopodial 
      growth cones by activating RhoA through the p75NTR signaling pathway.
FAU - Sun, Ying
AU  - Sun Y
AD  - Department of Human Physiology and Centre for Neuroscience, Flinders University, 
      Adelaide, Australia.
FAU - Lim, Yoon
AU  - Lim Y
FAU - Li, Fang
AU  - Li F
FAU - Liu, Shen
AU  - Liu S
FAU - Lu, Jian-Jun
AU  - Lu JJ
FAU - Haberberger, Rainer
AU  - Haberberger R
FAU - Zhong, Jin-Hua
AU  - Zhong JH
FAU - Zhou, Xin-Fu
AU  - Zhou XF
LA  - eng
PT  - Journal Article
PT  - Research Support, Non-U.S. Gov't
DEP - 20120427
PL  - United States
TA  - PLoS One
JT  - PloS one
JID - 101285081
RN  - 0 (Adaptor Proteins, Vesicular Transport)
RN  - 0 (Antibodies)
RN  - 0 (Brain-Derived Neurotrophic Factor)
RN  - 0 (Protein Precursors)
RN  - 0 (Receptors, Nerve Growth Factor)
RN  - 0 (Ngfr protein, mouse)
RN  - EC 3.6.5.2 (RhoA protein, mouse)
RN  - EC 3.6.5.2 (rho GTP-Binding Proteins)
RN  - EC 3.6.5.2 (rhoA GTP-Binding Protein)
RN  - Z020Y8WIJ4 (sortilin)
SB  - IM
MH  - Adaptor Proteins, Vesicular Transport/genetics/metabolism
MH  - Animals
MH  - Antibodies/pharmacology
MH  - Brain-Derived Neurotrophic Factor/antagonists & 
      inhibitors/pharmacology/*physiology
MH  - Cells, Cultured
MH  - Ganglia, Spinal/cytology/*drug effects/physiology
MH  - Gene Expression Regulation, Developmental/*physiology
MH  - Mice
MH  - Mice, Knockout
MH  - Nerve Fibers/drug effects/physiology
MH  - Neurites/drug effects/physiology
MH  - Protein Precursors/pharmacology/*physiology
MH  - Pseudopodia/drug effects/physiology
MH  - Receptors, Nerve Growth Factor/deficiency/genetics
MH  - Signal Transduction/physiology
MH  - Time-Lapse Imaging
MH  - rho GTP-Binding Proteins/*agonists/genetics/metabolism
MH  - rhoA GTP-Binding Protein
PMC - PMC3338794
COIS- Competing Interests: The authors have declared that no competing interests exist.
EDAT- 2012/05/05 06:00
MHDA- 2012/09/14 06:00
PMCR- 2012/04/27
CRDT- 2012/05/05 06:00
PHST- 2011/12/05 00:00 [received]
PHST- 2012/03/23 00:00 [accepted]
PHST- 2012/05/05 06:00 [entrez]
PHST- 2012/05/05 06:00 [pubmed]
PHST- 2012/09/14 06:00 [medline]
PHST- 2012/04/27 00:00 [pmc-release]
AID - PONE-D-11-24512 [pii]
AID - 10.1371/journal.pone.0035883 [doi]
PST - ppublish
SO  - PLoS One. 2012;7(4):e35883. doi: 10.1371/journal.pone.0035883. Epub 2012 Apr 27.