Thesis defense Miyuki Kuribara (Donders Series 53)

Environment-induced activation and growth of pituitary melanotrope cells of Xenopys laevis

Successful adaptation to a changing environment ensures the survival of the species. Maladaptation results in predation, malnutrition and disease. In the case of the South-African clawed toad Xenopus laevis, a change in the environmental light condition results in the adaptation of its skin color (‘camouflage'). Most remarkable during this adaptive process is the change in structure and functioning of its pituitary melanotrope cells, which produce melanophore-stimulating hormone (MSH), a peptide responsible for skin darkening. When the animal is on a dark background, the melanotropes double in size and produce about 10 times more of the MSH-precursor protein pro-opiomelanocortin (POMC) than when the animal is on a light background. As these changes are fully reversible, they clearly reflect a "cellular plasticity". Miyuki used the melanotrope cells as model of adaptation in the central nervous system and investigated what properties the melanotrope cells of X. laevis possess that makes them so plastic. She discovered that activated melanotropes not only release MSH but also brain-derived neurotrophic factor (BDNF) that plays a key autocrine role in stimulating melanotrope cell growth. In neurons, BDNF was already known as regulator of growth, survival and synaptic plasticity, but this is the first demonstration of a role of BDNF in the endocrine system. The stimulatory action of BDNF on the melanotrope is mediated by extracellular signal-regulated kinase (ERK), part of an intracellular pathway that mediates neurotrophin-induced growth in the brain. Miyuki also found that multiple factors are involved in the regulation of transcription of the POMC gene, including ERK, and established doublecortin-like kinase-short (DCLK-short) as down-stream effector of the ERK signal. DCLK-short has been assumed to be associated with BDNF-induced plasticity in the brain, but this is the first demonstration of its expression and function in the pituitary gland. Finally, by profiling the genes expressed in the highly activated melanotropes of black adapted Xenopus, Miyuki showed expression of heat shock- and other proteins that may be associated with cellular stress. This may provide novel insight into protective mechanisms operating in cells functioning under extreme conditions.