Abstract
Mutations of the von Hippel–Lindau (VHL) gene are associated with pheochromocytomas and paragangliomas, but the role of VHL in sympathoadrenal homeostasis is unknown. We generated mice lacking Vhl in catecholaminergic cells. They exhibited atrophy of the carotid body (CB), adrenal medulla, and sympathetic ganglia. Vhl-null animals had an increased number of adult CB stem cells, although the survival of newly generated neuron-like glomus cells was severely compromised. The effects of Vhl deficiency were neither prevented by pharmacological inhibition of prolyl hydroxylases or selective genetic down-regulation of prolyl hydroxylase-3, nor phenocopied by hypoxia inducible factor overexpression. Vhl-deficient animals appeared normal in normoxia but survived for only a few days in hypoxia, presenting with pronounced erythrocytosis, pulmonary edema, and right cardiac hypertrophy. Therefore, in the normal sympathoadrenal setting, Vhl deletion does not give rise to tumors but impairs development and plasticity of the peripheral O2-sensing system required for survival in hypoxic conditions.
Highlights
IntroductionMost neural crest-derived sympathetic precursor cells undergo c-jun-dependent apoptosis as the availability of trophic factors ( nerve growth factor) becomes limiting (Estus et al, 1994)
During embryogenesis, most neural crest-derived sympathetic precursor cells undergo c-jun-dependent apoptosis as the availability of trophic factors becomes limiting (Estus et al, 1994)
In vitro experiments on PC12 cells have suggested that the von Hippel–Lindau (VHL) protein might participate in the molecular cascade leading to apoptosis of sympathetic progenitor cells and that impairment of this protein could predispose to pheochromocytomas, a tumor of the adrenal gland, in adulthood (Lee et al, 2005)
Summary
Most neural crest-derived sympathetic precursor cells undergo c-jun-dependent apoptosis as the availability of trophic factors ( nerve growth factor) becomes limiting (Estus et al, 1994). In vitro experiments on PC12 cells have suggested that the von Hippel–Lindau (VHL) protein might participate in the molecular cascade leading to apoptosis of sympathetic progenitor cells and that impairment of this protein could predispose to pheochromocytomas, a tumor of the adrenal gland, in adulthood (Lee et al, 2005). Whereas loss of VHL protein can induce tumors in several organs, it negatively affects cell survival and proliferation in other tissues (Haase, 2005; Young et al, 2008; Li & Kim, 2011). Inactivation of VHL could have differing effects in cells of diverse embryological origin or developmental stage
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