The Role of Notch Signaling in Neurotransmitter Phenotype Specification in Xenopus Laevis

The development of a functional nervous system depends on individual neurons acquiring an appropriate neurotransmitter phenotype. In the developing spinal cord, neurons often display different fates in a salt and pepper pattern, and the mechanism by which this non-random dispersed patterning occurs remains largely unknown. However, given the role of Notch signaling in neurogenesis, the Notch pathway is a possible mediator because of its role in lateral inhibition. We hypothesized that Notch signaling is involved in the decision between GABAergic and glutamatergic fates and that activating Notch signaling in vivo would result in more neurons acquiring a glutamatergic neurotransmitter phenotype, while inactivating Notch signaling would increase GABAergic phenotypes. To test this hypothesis, we activated Notch signaling by injecting mRNA for X-Notch ICD and inactivated Notch signaling by injecting mRNA for xSu(H) DNA Binding Mutant, an inactive form of the transcription factor xSu(H). Embryos injected with X-Notch ICD lacked expression of the glutamate transporter xVGlut1 and the GABA transporter xGAT1, and embryos injected with xSu(H) DBM showed widespread ectopic expression of neuronal marker xNBT and xVGlut1. Embryos did not show ectopic expression of xSlug, suggesting that ectopic cells were not derived from the neural crest. HNK-1 immunohistochemistry showed ectopic expression in what appeared to be aberrant neural processes, indicating that the ectopic cells may be differentiated neurons or glia. We are now attempting to activate inducible xSu(H) DBM-GR and X-Notch ICD-GR at different developmental stages to determine the later effects of Notch activation, and if ectopic expression only occurs during a certain window of competency

Cortisol excess in chronic kidney disease – A review of changes and impact on mortality

Chronic kidney disease (CKD) describes the long-term condition of impaired kidney function from any cause. CKD is common and associated with a wide array of complications including higher mortality, cardiovascular disease, hypertension, insulin resistance, dyslipidemia, sarcopenia, osteoporosis, aberrant immune function, cognitive impairment, mood disturbances and poor sleep quality. Glucocorticoids are endogenous pleiotropic steroid hormones and their excess produces a pattern of morbidity that possesses considerable overlap with CKD. Circulating levels of cortisol, the major active glucocorticoid in humans, are determined by a complex interplay between several processes. The hypothalamic-pituitary-adrenal axis (HPA) regulates cortisol synthesis and release, 11β-hydroxysteroid dehydrogenase enzymes mediate metabolic interconversion between active and inactive forms, and clearance from the circulation depends on irreversible metabolic inactivation in the liver followed by urinary excretion. Chronic stress, inflammatory states and other aspects of CKD can disturb these processes, enhancing cortisol secretion via the HPA axis and inducing tissue-resident amplification of glucocorticoid signals. Progressive renal impairment can further impact on cortisol metabolism and urinary clearance of cortisol metabolites. Consequently, significant interest exists to precisely understand the dysregulation of cortisol in CKD and its significance for adverse clinical outcomes. In this review, we summarize the latest literature on alterations in endogenous glucocorticoid regulation in adults with CKD and evaluate the available evidence on cortisol as a mechanistic driver of excess mortality and morbidity. The emerging picture is one of subclinical hypercortisolism with blunted diurnal decline of cortisol levels, impaired negative feedback regulation and reduced cortisol clearance. An association between cortisol and adjusted all-cause mortality has been reported in observational studies for patients with end-stage renal failure, but further research is required to assess links between cortisol and clinical outcomes in CKD. We propose recommendations for future research, including therapeutic strategies that aim to reduce complications of CKD by correcting or reversing dysregulation of cortisol