Brain-Derived Neurotrophic Factor and Glial Cell Line-Derived Neurotrophic Factor Are Required Simultaneously for Survival of Dopaminergic Primary Sensory NeuronsIn Vivo

Abstract

Null mutations affecting members of the transforming growth factor-␤ and neurotrophin families result in overlapping patterns of neuronal cell death. This is particularly striking in the cranial sensory nodose-petrosal ganglion complex (NPG), in which loss of either glial cell line-derived neurotrophic factor (GDNF), brain-derived neurotrophic factor (BDNF), neurotrophin-3 (NT-3), or neurotrophin-4 (NT-4) results in a 30-50% reduction in neuronal survival. It is unknown, however, whether GDNF and any single neurotrophin support survival of the same cells, and if so, whether they are required simultaneously or sequentially during development. To approach these issues we defined survival requirements of nodose and petrosal neurons for GDNF in vitro and in bdnf, gdnf, and bdnf/gdnf null mutant mice, as well as the distribution of GDNF in NPG target tissues. Our analyses focused on the total population of ganglion cells as well as the subset of NPG neurons that are dopaminergic.Neuron losses in bdnf/gdnf double mutants are not additive of the losses in single bdnf or gdnf null mutants, indicating that many cells, including dopaminergic neurons, require both GDNF and BDNF for survival in vivo. Moreover, both factors are required during the same period of development, between embryonic day (E) 15.5 and E17.5. In addition, GDNF, like BDNF is expressed in target tissues at the time of initial target innervation and coincident with GDNF dependence of the innervating neurons. Together, these findings demonstrate that both GDNF and BDNF can act as target-derived trophic factors and are required simultaneously for survival of some primary sensory neurons. Key words: GDNF; BDNF; primary sensory neurons; growth factors; neurotrophins; knock-out mice; nodose ganglion; petrosal ganglion; carotid bodyGlial cell line-derived neurotrophic factor (GDNF) and the related proteins neurturin, persephin, and artemin, comprise a subgroup of the transforming growth factor-␤ superfamily of growth and differentiation factors. The GDNF family members signal through a receptor complex consisting of a ligand-specific glycosyl-phosphatidylinositol-linked binding molecule (GFR␣) and the membrane-spanning RET (rearranged during transfection) receptor tyrosine kinase (Rosenthal, 1999;Baloh et al., 2000). GDNF supports survival of a variety of peripheral and central neurons in vitro, including midbrain dopaminergic, spinal motor, sympathetic, parasympathetic, peripheral sensory, and enteric neurons (for review, see Unsicker et al., 1998). However, analysis of GDNF or GFR␣1 knock-out mice has revealed that a more restricted subset of neurons requires GDNF for survival in vivo Pichel et al., 1996;Sanchez et al., 1996;Cacalano et al., 1998).One of the most severely affected neuronal populations in GDNF knock-out mice is the nodose-petrosal ganglion complex (NPG) of primary cranial sensory neurons, in which 40% of cells die by birth . Interestingly, targeted disruption of the genes encoding brain-derived neurotrophic factor (BDNF) (Ernfors et al., 1994...

Selective Glial Cell Line-Derived Neurotrophic Factor Production in Adult Dopaminergic Carotid Body CellsIn Situand after Intrastriatal Transplantation

“…Selective expression of GDNF in CB glomus cells of adult rodents GDNF is expressed in several tissues during development, and its presence in the embryonic and newborn CB has been reported previously (Nosrat et al, 1996;Lipton et al, 1999;Erickson et al, 2001). However, unequivocal evidence for GDNF expression in CB of adult rodents was obtained from heterozygous knock-out GDNF/lacZ mice, in which the cells expressing GDNF contain ␤-galactosidase deposits that can be labeled with the characteristic blue X-gal staining .…”

“…Therefore, glomus cells are ideal candidates to be used as biological pumps for the controlled endogenous release of GDNF and probably other trophic factors with unique synergistic actions. In fact, CB tissue contains BDNF (Erickson et al, 2001), and CB grafting has also been shown to reduce neuronal death in an acute rat stroke model (Yu et al, 2004). A limitation for the clinical use of glomus cell autotransplants in PD might be the small size of the CB, which probably synthesizes less GDNF than is necessary for advanced PD patients (Arjona et al, 2003).…”

Valproate protects dopaminergic neurons in midbrain neuron/glia cultures by stimulating the release of neurotrophic factors from astrocytes

“…12 An in vivo study also showed that the loss of DA neurons with double mutants of BDNF and GDNF is nonadditive, compared with BDNF or GDNF single null mutant. 41 We then used real-time PCR to quantify the expression of BDNF in astrocytes after VPA treatment. Results showed that VPA treatment also caused a time-dependent increase in BDNF mRNA levels.…”

Dopaminergic Differentiation of Human Embryonic Stem Cells

“…Markers for mature dopamine neurons thus include proteins directly involved in dopamine neurotransmitter biosynthesis and function, especially TH, AADC, DHPR, GTPCH, and DAT. Dopamine neurons also respond to the growth factors BDNF and GDNF [43][44][45][46]. The receptor for BDNF is Trkb [47,48].…”