Mechanisms underlying pituitary hypoplasia and failed cell specification in Lhx3-deficient mice

AbstractThe LIM homeodomain transcription factor, LHX3, is essential for pituitary development in mouse and man. Lhx3 engineered null mice have profound pituitary hypoplasia that we find is attributable to an increase in cell death early in pituitary development. Dying cells are localized to regions of TPIT expression indicating that cell death may contribute to the severe reduction in differentiated corticotrope cells and lower expression of the corticotrope transcription factors, TPIT and NEUROD1. Lhx3 deficiency also results in dorsal ectopic expression of transcription factors characteristic of gonadotropes, SF1 and ISL1, but no gonadotropin expression. This apparent disturbance of cell differentiation may be due, in part, to loss of NOTCH2. NOTCH2 is normally expressed in the pituitary at the boundary between dorsal, proliferating cells and ventral, differentiating cells and is important for maintaining dorsal–ventral patterning in other organs. Thus, Lhx3 contributes significantly to pituitary development by maintaining normal dorsal–ventral patterning, cell survival, and normal expression of corticotrope-specific transcription factors, which are necessary for repressing ectopic gonadotrope differentiation

Oxr1 Is Essential for Protection against Oxidative Stress-Induced Neurodegeneration

Oxidative stress is a common etiological feature of neurological disorders, although the pathways that govern defence against reactive oxygen species (ROS) in neurodegeneration remain unclear. We have identified the role of oxidation resistance 1 (Oxr1) as a vital protein that controls the sensitivity of neuronal cells to oxidative stress; mice lacking Oxr1 display cerebellar neurodegeneration, and neurons are less susceptible to exogenous stress when the gene is over-expressed. A conserved short isoform of Oxr1 is also sufficient to confer this neuroprotective property both in vitro and in vivo. In addition, biochemical assays indicate that Oxr1 itself is susceptible to cysteine-mediated oxidation. Finally we show up-regulation of Oxr1 in both human and pre-symptomatic mouse models of amyotrophic lateral sclerosis, indicating that Oxr1 is potentially a novel neuroprotective factor in neurodegenerative disease