Death Receptor 5 and Neuroproliferation

Abstract

Tumor necrosis factor-related apoptosis-inducing ligand or Apo2 ligand is a member of the tumor necrosis factor superfamily of cytokines that induces apoptosis upon binding to its death domain-containing transmembrane receptors, death receptors 4 and 5 (DR4, DR5). However, DR5 is also expressed in the developing CNS where it appears to play a role unrelated to apoptosis, and instead may be involved in the regulation of neurogenesis. We report on the distribution of DR5 expression in mouse hippocampus, cerebellum, and rostral migratory stream (RMS) of olfactory bulb from embryonic (E) day 16 (E16) to postnatal (P) day (P180). At E16, DR5-positive cells were distributed widely in embryonic hippocampus with strong immunostaining in the developing dentate gyrus. In newborn hippocampus, DR5-positive cells were predominantly located in proliferative zones, such as dentate gyrus, subventricular zone, and RMS. After postnatal day 7 (P7), the number of DR5-positive cells decreased, and cells with intense fluorescence were primarily restricted to the subgranular layer (SGL), although the granular cell layer showed weak fluorescence. After P30, only few DR5-positive cells were found in SGL, and mature granule cells were negative for DR5 expression. To address whether DR5 expression is a restricted to progenitor cells and newborn neurons, we performed 5-bromo-deoxyuridine labeling. We report that proliferative cells in the SGL selectively express DR5, with lower levels of expression in cells positive for doublecortin, a marker of newborn neurons. In addition, the stem cells in intestine, cerebellum, and RMS were also demonstrated to be DR5-positive. In the meantime, in cerebellum, DR5-positive cells were also positive for glial fibrillary acidic protein, a marker of proliferative Bergmann cells. We conclude that DR5 is selectively expressed by neuroprogenitor cells and newborn neurons, suggesting that the DR5 death receptor is likely to play a key role in neuroproliferation and differentiation.

Compartmentalization of TNF-related apoptosis-inducing ligand (TRAIL) death receptor functions: emerging role of nuclear TRAIL-R2

“… 30 Correspondingly, high intracellular expression of TRAIL-R2 has been demonstrated for stem cells at the base of the intestinal crypts in the small intestine. 31 …”

“…Few relatively recent studies show the localization of TRAIL receptors in the nucleus ( Tables 1 and 2 ). 16 , 27 , 31 , 59 , 65 , 67 , 68 , 69 An early report on the melanoma cell line, Mel-FH, demonstrated TRAIL-R1 as predominantly expressed in the nucleus, where it colocalized with TRAIL-R3 and TRAIL-R4. 65 Nuclear presence of TRAIL-R1 and TRAIL-R2 has also been shown for normal and psoriatic skin, with nTRAIL-R2 being more strongly expressed in psoriatic lesions and in the dermis of psoriatic skin compared with healthy skin.…”

“…In one report, the pattern of intracellular distribution of TRAIL-R during the development of the mouse CNS was studied. The authors demonstrated that the expression of TRAIL-R was not only restricted to proliferating zones but, importantly, was mainly located in the cell nuclei, suggesting a specific, proliferation-associated function of nTRAIL-R. 31 Another study investigating human nuclear TRAIL receptors finally uncovered specific functions of nTRAIL-R2 connecting this receptor to the process of miRNA maturation ( Figure 2 ). 16 Briefly, in several different tumor cells, nTRAIL-R2 interacts with the core Microprocessor complex Drosha/DGCR8 and with several of its accessory proteins, p68, NF45 and hnRNPA1.…”

Activation of TRAIL‐DR5 pathway promotes sensorineural degeneration in the inner ear

“…In the brain, TRAIL‐DR5 signaling controls not only cell death (Uberti et al ., 2007; Cui et al ., 2010), but also inflammation (Hoffmann et al ., 2009) and neuroproliferation and differentiation (Niu et al ., 2012). …”