While the mammalian retina is well understood at the anatomical and physiological levels, little is known about the mechanisms that give rise to the retina's highly ordered pattern or its diverse neuronal cell types. Previous investigations have shown that gene disruption of the POU-IV class transcription factor Brn-3b (Brn-3.2) resulted in the loss of most retinal ganglion cells in retinas of postnatal mice. Here, we used lacZ and human placental alkaline phosphatase genes knocked into the brn-3b locus to follow the fate of brn-3b-mutant cells in the developing retina. We found that Brn-3b was not required for the initial commitment of retinal ganglion cell fate or for the migration of ganglion cells to the ganglion cell layer. However, Brn-3b was essential for the normal differentiation of retinal ganglion cells; without it, the cells underwent enhanced apoptosis. Retinal ganglion cells lacking brn-3b extended processes at the appropriate time in development, but these processes were disorganized, resulting in a thinner optic nerve. Explanted retinas from brn-3b-null embryos also extended processes when cultured in vitro, but the processes were shorter and less bundled than in wild-type retinas. Ultrastructural and marker analyses showed that the processes of mutant ganglion cells had dendritic rather than axonal features, suggesting that mutant cells formed dendrites in place of axons. These results suggest that Brn-3b regulates the activity of genes whose products play essential roles in the formation of retinal ganglion cell axons.
bBrown fat generates heat through uncoupled respiration, protecting against hypothermia and obesity. Adult humans have brown fat, but the amounts and activities are substantially decreased in obesity, by unknown mechanisms. Here we show that elevated microRNA 34a (miR-34a) in obesity inhibits fat browning in part by suppressing the browning activators fibroblast growth factor 21 (FGF21) and SIRT1. Lentivirus-mediated downregulation of miR-34a in mice with diet-induced obesity reduced adiposity, improved serum profiles, increased the mitochondrial DNA copy number, and increased oxidative function in adipose tissue in both BALB/c and C57BL/6 mice. Remarkably, downregulation of miR-34a increased coexpression of the beige fat-specific marker CD137 and the browning marker UCP1 in all types of white fat, including visceral fat, and promoted additional browning in brown fat. Mechanistically, downregulation of miR-34a increased expression of the FGF21 receptor components, FGFR1 and KL, and also that of SIRT1, resulting in FGF21/SIRT1-dependent deacetylation of PGC-1␣ and induction of the browning genes Ucp1, Pgc-1␣, and Prdm16. Importantly, anti-miR-34a-mediated beneficial effects, including decreased adiposity, are likely from multiple tissues, since downregulation of miR-34a also improves hepatic FGF21 signaling and lipid oxidation. This study identifies miR-34a as an inhibitor of beige and brown fat formation, providing a potential target for treating obesity-related diseases.T he global epidemic of obesity has greatly increased research interest in adipose biology, particularly that of energy-dissipating brown fat (1). While white adipose tissue (WAT) stores excess chemical energy, leading to weight gain, brown adipose tissue (BAT) expends energy as heat through uncoupled respiration via the action of mitochondrial uncoupled protein 1 (UCP1), protecting against hypothermia and obesity (2-5). Recent studies discovered a second type of brown-like fat, "beige fat," which is present in WAT and is genetically distinct from classical BAT (6). Interestingly, recent human studies using 2-fluorodeoxyglucose coupled with positron-emission tomography (PET) scanning showed that adult humans have brown fat and that the activities and amounts of brown fat are inversely related to the body mass index (BMI) and substantially decreased in obesity (3, 7). Increasing energy expenditure by promoting production of brown fat in BAT and also beige fat in WAT, particularly in obese individuals, would be an appealing option for weight reduction and for treating obesity-related diseases.Brown and beige fat depots develop in response to various activators, including cold exposure, hormones, exercise, and transcriptional regulators, such as PRDM16, PPAR␥, SIRT1, and PGC-1␣ (8-11). Fibroblast growth factor 21 (FGF21) has been shown to beneficially affect metabolism and energy balance by enhancing fatty acid -oxidation during prolonged fasting and also by promoting fat browning in WAT, as well as in BAT, in response to cold exposure in mice (1...
Purpose Recurrent glioblastoma multiforme (GBM) is characterized by resistance to radiotherapy and chemotherapy and a poor clinical prognosis. In this study, we investigated the role of the oncogenic transcription factor FoxM1 in GBM cells’ resistance to TMZ and its potential molecular mechanism. Experimental Design FoxM1 expression levels were measured by immunohistochemical analysis in 38 pairs of primary and recurrent GBM tumor samples. Expression levels were also measured in primary recurrent GBM cell lines, and their responses to TMZ were characterized. In a mechanistic study, an siRNA array was used to identify downstream genes, and a chromatin immunoprecipitation assay was used to confirm transcriptional regulation. Results Recurrent tumors that were TMZ resistant expressed higher levels of FoxM1 than did primary tumors. Recurrent GBM cell lines expressed higher levels of FoxM1 and the DNA damage repair gene Rad51 and were resistant to TMZ. TMZ treatment led to increased FoxM1 and Rad51 expression. FoxM1 knockdown inhibited Rad51 expression and sensitized recurrent GBM cells to TMZ cytotoxicity. FoxM1 directly regulated Rad51 expression through two FoxM1-specific binding sites in its promoter. Rad51 re-expression partially rescued TMZ resistance in FoxM1-knockdown recurrent GBM cells. A direct correlation between FoxM1 expression and Rad51 expression was evident in recurrent GBM tumor samples. Conclusion Targeting the FoxM1-Rad51 axis may be an effective method to reverse TMZ resistance in recurrent GBM.
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