Egr-1 and Hipk2 are required for the TrkA to p75NTR switch that occurs downstream of IGF1-R

Abstract

The aging program mediated by IGF1-R is responsible for a naturally occurring TrkA-to-p75 NTR switch that leads to activation of the second messenger ceramide and increased production of the Alzheimer's disease amyloid β-peptide. Biochemical and genetic approaches that target IGF1-R signaling, p75 NTR , or ceramide are able to block the above events. Here, we show that the transcription factors Egr-1 and Hipk2 are required elements for the TrkA-to-p75 NTR switch downstream of IGF1-R signaling. Specifically, Egr-1 is required for the upregulation of p75 NTR , whereas Hipk2 is required for the downregulation of TrkA. In fact, gene silencing of Egr-1 abolished the ability of IGF1 to upregulate p75 NTR , whereas similar approaches directed against Hipk2 blocked the downregulation of TrkA. In addition, IGF1 treatment favored binding of Egr-1 and Hipk2 to the promoter of p75 NTR and TrkA, respectively. Finally, the expression levels of both Egr-1 and Hipk2 are upregulated in an age-dependent fashion. Such an event is opposed by caloric restriction, a model of delayed aging, and favored by the p44 transgene in p44 +/+ animals, a model of accelerated aging.

Sphingosine but not Sphingosine-1-phosphate Stimulates Suicidal Erythrocyte Death

“…Ceramide stimulates the death of a wide variety of cells including neurons [67][68][69], Tlymphocytes [70], hepatocytes [71], epithelial cells [72] and erythrocytes [30,42,44,71,73]. Sphingolipids participate in cancer [64,[74][75][76][77][78][79], inflammatory disease [52,56,80,81] including lung inflammation and infection [82], cystic fibrosis [83], cardiovascular disease [84][85][86], Wilson´s disease [71], diabetes [87][88][89][90] and several neurological diseases [17,18,67,[91][92][93][94].…”

Expression, regulation and function of Egr1 during implantation and decidualization in mice

“…This data was consistent with those of previous studies in the cardiac fibroblasts, SH-SY5Y cells and vascular smooth muscle cells. [53][54][55] In conclusion, Egr1 may play an important role during mouse embryo implantation and decidualization.…”

“…In order to collect preimplantation embryos, the female mice were caged with fertile male mice after hCG injection. The embryos at the stages of zygote, 2-cell, 4-cell, 8-cell, morula and blastocyst were recovered by flushing oviducts or uterus at 23,42,54,68,80, and 92 h post-hCG injection. Oocytes and zygotes were digested with 300 IU hyaluronidase in Dulbecco's phosphate-buffered saline (D-PBS) to remove cumulus cells.…”

Early Development of the Vertebrate Inner Ear

“…IGF‐I actions and IGF1R expression are mediated by an intracellular signaling network (Murillo‐Cuesta et al, 2011, 2012; Fig. 6), and precedes that of neurotrophins and TrkA expression in neurons (Li et al, 2009). Indeed, otic neurons gradually reduce their expression of the Igf1r , while they increase the neurotrophin receptor TrkC (Aburto et al, 2012), suggesting that IGF‐I is a key trophic factor during the otic neuronal progenitor phase of early inner ear development.…”

“…Indeed, mutations in miR‐96 cause hearing loss in mice and men (Lewis et al, 2009; Mencía et al, 2009). The dynamic expression of the miR‐183 family in the mouse begins at the otocyst stage and has the higher expression in differentiating hair cells, suggesting that this family is involved in hair cell differentiation and maturation (SacheLi et al, 2009). Another miRNA family, the miR‐200 (miR‐200a, miR‐200b, miR‐200c, miR‐141, and miR‐429) has been associated to inner ear prosensory specification.…”