Survival and differentiation of central noradrenergic neurons
Author: Holm, Pontus
Date: 2002-08-30
Location: Centrum för Molekylär Medicin (CMM) L8:00, Karolinska Sjukhuset
Time: 9.00
Department: Institutionen för medicinsk biokemi och biofysik (MBB) / Department of Medical Biochemistry and Biophysics
Abstract
About half of all central noradrenergic (NA) neurons reside in the locus
coeruleus (LC). Projections from the LC reach target regions throughout
the entire brain and regulate a variety of functions, such as mood,
vigilance, arousal, sleep, attention and memory acquisition. The
development of LC noradrenergic neurons is severely affected by
reductions in the availability of BMPs in vivo, and by the lack of the
basic helix-loophelix protein Mash1, or the Phox2a, Phox2b or Rnx
homeodomain proteins, as shown in null mutant mice.
To produce NA neurons we generated neural stem cell clones with stable
overexpression of Mash1 or Phox2b and treated them with combinations of
BDNF, NT-4, BMPs and FGF to induce a noradrenergic phenotype, but no TH
expression was detected.
To characterize the survival requirements of developing LC neurons, we
examined the involvement of rhombomere I patterning proteins. FGF8, BMP2,
BMP5 and BMP7 were able to increase the number of TH positive LC neurons
in E13.5 LC cultures. Of all the Writs expressed in the first rhombomere
by E12.5 in mice, Wnt5a was the only one that was expressed in the
vicinity of the LC and Wnt5a increased the survival of TH positive
neurons in LC cultures. These results suggest that patterning signals of
rhombomere I may work as survival factors in the LC at later stages of
development.
Analysis of GDNF and NT-3 double null mutant mice revealed no LC
abnormalities, just as in the individual knockouts. Treatment of E13.5 LC
cultures with GDNF, NTN and NT-3 did not affect LC neuron survival,
suggesting that these molecules are not essential for embryonic LC
development. However, we show, both in vivo and in vitro, that GDNF and
NTN are neuritogenic factors for LC noradrenergic neurons.
The two neurotrophins NT-4 and BDNF and their preferred receptor, TrkB,
were studied for their role in LC development. We conclude that they play
critical roles for the survival and phenotypic differentiation of
developing LC noradrenergic neurons, possibly by linking the CREB and the
Mash1-Phox2 pathways of catecholaminergic phenotype induction. TrkB is
expressed in the developing mouse LC and TrkB knockout mice suffer
deficient LC development. BDNF and NT-4 dramatically increase the number
of TH and Phox2a immunoreactive neurons in E 13.5 rat LC primary
cultures.
Examination of more mature LC neurons (E15) treated with BMP2 and/or
forskolin suggested that stimulation of these cells by BMPs and cAMP
plays an important role in conferring NA neurons responsiveness to
several trophic factors.
List of papers:
I. Reiriz J, Holm PC, Alberch J, Arenas E (2002). "BMP-2 and cAMP elevation confer locus coeruleus neurons responsiveness to multiple neurotrophic factors. " J Neurobiol 50(4): 291-304
Pubmed
II. Holm PC, Akerud P, Wagner J, Arenas E (2002). "Neurturin is a neuritogenic but not a survival factor for developing and adult central noradrenergic neurons. " J Neurochem 81(6): 1318-27
Pubmed
III. Holm PC, Rodriguez FJ, Kresse A, Canals JM, Silos-Santiago I, Arenas E (2002). "Critical role of TrkB ligands in the survival and phenotypic differentiation of developing locus coeruleus noradrenergic neurons." (Submitted)
IV. Holm PC, Rodriguez JX, Kele J, Castelo-Branco G, Arenas E (2002). "Role of BMPs, FGF-8 and Wnts in the development of locus coeruleus noradrenergic neurons." (Submitted)
I. Reiriz J, Holm PC, Alberch J, Arenas E (2002). "BMP-2 and cAMP elevation confer locus coeruleus neurons responsiveness to multiple neurotrophic factors. " J Neurobiol 50(4): 291-304
Pubmed
II. Holm PC, Akerud P, Wagner J, Arenas E (2002). "Neurturin is a neuritogenic but not a survival factor for developing and adult central noradrenergic neurons. " J Neurochem 81(6): 1318-27
Pubmed
III. Holm PC, Rodriguez FJ, Kresse A, Canals JM, Silos-Santiago I, Arenas E (2002). "Critical role of TrkB ligands in the survival and phenotypic differentiation of developing locus coeruleus noradrenergic neurons." (Submitted)
IV. Holm PC, Rodriguez JX, Kele J, Castelo-Branco G, Arenas E (2002). "Role of BMPs, FGF-8 and Wnts in the development of locus coeruleus noradrenergic neurons." (Submitted)
Issue date: 2002-08-09
Publication year: 2002
ISBN: 91-7349-277-9
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