Fibroblast growth factor‐2 converts PACAP growth action on embryonic hindbrain precursors from stimulation to inhibition

Abstract

Pituitary adenylyl cyclase activating peptide (PACAP) has been shown either to stimulate or to inhibit neural cell proliferation depending on the origin of the cell population. We show here that, depending on the presence or absence of fibroblast growth factor-2 (FGF-2, also called basic FGF), PACAP may either stimulate or inhibit DNA synthesis in neural precursors isolated from embryonic day 10.5 mouse hindbrain. In the absence of FGF-2, PACAP stimulated 3H-thymidine incorporation in a dose-dependent manner. This stimulatory action was unaffected by antagonists of protein kinases A and C but was abolished in the presence of the MEK1/2 antagonist PD98059. In contrast, when FGF-2 was present, PACAP inhibited DNA synthesis. This inhibitory action was insensitive to PD98059 but was fully blocked by the protein kinase A (PKA) inhibitor H89. The differential blockades by MEK1/2 and PKA inhibitors indicate that the FGF-2-induced switch in PACAP action on DNA synthesis was accomplished by a change in PACAP signaling pathways. We hypothesize that the actions of PACAP in the specific parts of the developing nervous system are determined in part by the presence or absence of FGFs and other growth factors.

Multiple Actions of Pituitary Adenylyl Cyclase Activating Peptide in Nervous System Development and Regeneration

“…VPAC 1 and/or VPAC 2 genes also appear to be expressed in several germinal regions of the developing nervous system, but generally at levels considerably lower than that of PAC 1 . In mouse E10.5 hindbrain, VPAC 1 and VPAC 2 mRNAs were below the level of detection by in situ hybridization, but were detected in RNA extracts from this region by RT-PCR [29]. In the rat, VPAC 1 gene transcripts were detected at low levels in germinal zones by in situ hybridization, and in derived cultures by RT-PCR [27].…”

“…Effects of VIP in these cultures included increased neuroblast mitosis, enhanced survival of both dividing and nondividing cells, and increased neurite outgrowth [47,48]. Interestingly, the survival effect of VIP was significantly lower in cultures obtained from later-stage embryos or from postnatal animals, whereas the [31][32][33] increased decreased increased trkB, BDNF Hindbrain neuroblasts [20,29] dual action 2 Cerebellar granule neurons [34][35][36][37][38] increased increased increased Olfactory neuron precursors [39] increased increased Sensory neurons [40] increased increased Motor neurons [41] increased Midbrain dopamine neurons [42] increased Forebrain cholinergic neurons [43] increased Oligodendrocyte precursors [28] increased Astrocytes [44,45] increased interleukin-6 Microglia [46] TNF· BDNF = Brain-derived neurotrophic factor; TNF· = tumor necrosis factor ·.…”

Chronic Mild Stress during Gestation Worsens Neonatal Brain Lesions in Mice

“…Brains were removed, and cortex and underlying white matter immediately adjacent to the normal site of excitotoxin injection (see above) were rapidly dissected from the different animals for RNA extraction. Total RNA was extracted as described previously (Lelievre et al, 2002), followed by DNaseI. For each sample, 600 ng were used in reverse transcription (iScript kit; Bio-Rad, Hercules, CA).…”

Analysis of Gene Expression in the Normal and Malignant Cerebellum

“…To date, most studies of PACAP in the cerebellum have indicated that it increases proliferation of GCPs and promotes survival in the presence of various death-inducing stimuli (Vaudry et al, 1999(Vaudry et al, ,2002Tabuchi et al, 2001). On the other hand, recent studies of neurons in the embryonic cortex and hindbrain indicate that PACAP can inhibit proliferation of those cells (Suh et al, 2001;Lelievre et al, 2002). Thus, PACAP might contribute to cell-cycle exit in the cerebellum as well.…”