BMP-2 and cAMP elevation confer locus coeruleus neurons responsiveness to multiple neurotrophic factors

J Neurobiol. 2002 Mar;50(4):291-304. doi: 10.1002/neu.10034.


The locus coeruleus (LC) is a major target of several neurodegenerative disorders, including Parkinson's and Alzheimer's diseases. However, very little is known of the trophic requirements of LC neurons. In the present work, we have studied the biological activity of neurotrophic factors from different families in E15 primary cultures of LC neurons. In agreement with previous results, neurotrophin-3 (NT-3) and also glial cell line- derived neurotrophic factor (GDNF) increased the number of embryonic LC noradrenergic neurons in the presence of serum. In serum-free conditions, none of the factors tested, including NT-3, GDNF, neurturin, basic fibroblast growth factor (bFGF), or bone morphogenetic protein-2 (BMP-2), promoted the survival of tyrosine hydroxylase (TH)-immunoreactive neurons at 6 days in vitro. However, when BMP-2 was coadministered with any of these factors the number of LC TH-positive neurons increased twofold. Similar results were obtained by cotreatment of LC neurons with forskolin and NT-3, bFGF, or BMP-2. The strongest effect (a fourfold increase in the number of TH-positive cells) was induced by cotreatment with forskolin, BMP-2, and GDNF. Thus, our results show that LC neurons require multiple factors for their survival and development, and suggest that activation of LC neurons by bone morphogenetic proteins and cAMP plays a decisive role in conferring noradrenergic neuron responsiveness to several trophic factors.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Bone Morphogenetic Protein 2
  • Bone Morphogenetic Proteins / metabolism*
  • Bone Morphogenetic Proteins / pharmacology
  • Cell Differentiation / drug effects
  • Cell Differentiation / physiology*
  • Cell Survival / drug effects
  • Cell Survival / physiology*
  • Colforsin / pharmacology
  • Culture Media, Serum-Free / pharmacology
  • Cyclic AMP / metabolism*
  • Cyclic AMP / pharmacology
  • Drug Interactions / physiology
  • Female
  • Fetus
  • Locus Coeruleus / drug effects
  • Locus Coeruleus / embryology*
  • Locus Coeruleus / metabolism
  • Nerve Growth Factors / metabolism*
  • Nerve Growth Factors / pharmacology
  • Neurons / drug effects
  • Neurons / metabolism*
  • Norepinephrine / metabolism*
  • Phenotype
  • Pregnancy
  • Rats
  • Rats, Sprague-Dawley
  • Transforming Growth Factor beta*
  • Up-Regulation / drug effects
  • Up-Regulation / physiology


  • Bmp2 protein, rat
  • Bone Morphogenetic Protein 2
  • Bone Morphogenetic Proteins
  • Culture Media, Serum-Free
  • Nerve Growth Factors
  • Transforming Growth Factor beta
  • Colforsin
  • Cyclic AMP
  • Norepinephrine