Jenks BG et al. (2012), The role of brain-derived neurotrophic factor i...

XB-ART-44732

Gen Comp Endocrinol 2012 Jul 01;1773:315-21. doi: 10.1016/j.ygcen.2012.01.001.

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The role of brain-derived neurotrophic factor in the regulation of cell growth and gene expression in melanotrope cells of Xenopus laevis.

Jenks BG , Kuribara M , Kidane AH , Kramer BM , Roubos EW , Scheenen WJ .

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Brain-derived neurotrophic factor (BDNF) is, despite its name, also found outside the central nervous system (CNS), but the functional significance of this observation is largely unknown. This review concerns the expression of BDNF in the pituitary gland. While the presence of the neurotrophin in the mammalian pituitary gland is well documented its functional significance remains obscure. Studies on the pars intermedia of the pituitary of the amphibian Xenopus laevis have shown that BDNF is produced by the neuroendocrine melanotrope cells, its expression is physiologically regulated, and the melanotrope cells themselves express receptors for the neurotrophin. The neurotrophin has been shown to act as an autocrine factor on the melanotrope to promote cell growth and regulate gene expression. In doing so BDNF supports the physiological function of the cell to produce and release α-melanophore-stimulating hormone for the purpose of adjusting the animal's skin color to that of its background.

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Species referenced: Xenopus laevis
Genes referenced: adcyap1 bdnf creb1 crh fos kcnip3 mapk1 npy nr4a1 ntrk2 pomc vipr1

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	Fig. 1. Schematic overview of the regulation of the melanotrope cell of Xenopus laevis. The secretion of α-MSH is regulated by multiple neurotransmitters, some of which are indicated in the figure, together with their receptors that activate (cyan) or inhibit (red) adenylyl cyclase. Cyclic-AMP binds to the regulatory subunit (R) of PKA leading to the dissociation of the catalytic subunit (C) which then activates components of Ca2+ signaling machinery on the plasma membrane, resulting in opening of voltage-operated Ca2+ channels (VOCC) and influx of Ca2+. This Ca2+ signal stimulates exocytosis and mobilizes intracellular Ca2+ stores to initiate a self-propagating wave of Ca2+ that ultimately enters the nucleus. In the nucleus Ca2+ and the catalytic subunit of PKA are responsible for activating transcription factors (e.g. CREB, USF1/2, CaRF1) that act on responsive elements (grey boxes) within the promoters of various genes. Among the first genes to be activated are the immediate early genes c-Fos and Nur77, along with BDNF, POMC and proBDNF mRNA are translated at the rough endoplasmic reticulum (RER) and co-packaged into secretory granules. Mature BDNF acts as an autocrine factor, with TrkB signaling activating ERK that subsequently phosphorylates DCLK-short to translocate into the nucleus. In the nucleus DCLK-short stimulates, through unknown pathways, the expression of POMC; it is likely also involved in the regulation of other genes, such as those governing cell growth. ERK may act via Nur77 on POMC expression, possibly in a compartment regulated by PKA associated with AKAP. Abbreviations: AKAP, A kinase-associated protein; AP1, activator protein 1 promoter site; BDNF, brain-derived neurotrophic factor; β, β-adrenergic receptor; β/γ, β/γ subunit of G proteins; CaRE, calcium-responsive element; CaRF, calcium-responsive transcription factor; CRE, cyclic-AMP-responsive element; CRH, corticotropin-releasing hormone; D2, dopamine D2 receptor; DCLK, doublecortin-like kinase; DRE, down-stream responsive element; DREAM, DRE antagonist modulator; ERK, extracellular-signal-regulated kinase; Gb, GABAb receptor; NPY, neuropeptide Y; PACAP, pituitary adenylate cyclase-activating polypeptide; POMC, proopiomelanocortin; PLCγ, phospholipase Cγ; PKA, protein kinase A; R1, CRH receptor 1; USF, upstream stimulatory factor; V1, VPAC1 receptor; VOCC, voltage-operated Ca2+ channel; Y1, NPY Y1 receptor. (Adapted from Kidane [33] and Kuribara [43].
	Fig. 2. (A) Schematic representation of the Xenopus BDNF gene showing its promoter (P) specific transcripts (T1–T7). Each transcript possesses the pre–proBDNF coding exon VII (dark blue indicates BDNF coding region within the exon). Transcript VII is a 5′ extension of exon VII (VII 5′ext). AUG codons upstream of the AUG start codon for pre–proBDNF are indicated by vertical red lines within the exons. (B) Effect of transfer of white-background adapted Xenopus to a black background on the relative level of BDNF transcripts IV and VII. For both, the level of mRNA in white background control animals (WA) was set at 1. Black-adapted (BA) control animals stayed minimally 3 weeks on black background. Data are ±SEM (n = 5) and asterisks indicate significant difference from the WA-group. ∗P < 0.005; ∗∗P < 0.0005 (data from Kidane et al. [35]).
	Fig. 3. Scheme of strategies used to block (yellow bolt) the action of endogenous BDNF released from the Xenopus melanotrope cell, together with effects of each treatment on the in vitro growth of the melanotropes, as assessed by determining cell diameter. Cells from black-adapted Xenopus were incubated for 3 days in complete medium or in medium containing either antiserum to BDNF or TrkB fragment (each to sequester released BDNF), cyclotraxin-B (to block BDNF binding to TrkB) or U0126 (to block BDNF signaling through MAPK). Asterisks indicate significant difference with the control group at 0 days (P < 0.05; n = 3) (data from Kuribara et al. [46]).