Resistance to chemical carcinogenesis induction via a dampened inflammatory response in naked mole-rats.

Naked mole-rats (NMRs) have a very low spontaneous carcinogenesis rate, which has prompted studies on the responsible mechanisms to provide clues for human cancer prevention. However, it remains unknown whether and how NMR tissues respond to experimental carcinogenesis induction. Here, we show that NMRs exhibit extraordinary resistance against potent chemical carcinogenesis induction through a dampened inflammatory response. Although carcinogenic insults damaged skin cells of both NMRs and mice, NMR skin showed markedly lower immune cell infiltration. NMRs harbour loss-of-function mutations in RIPK3 and MLKL genes, which are essential for necroptosis, a type of necrotic cell death that activates strong inflammation. In mice, disruption of Ripk3 reduced immune cell infiltration and delayed carcinogenesis. Therefore, necroptosis deficiency may serve as a cancer resistance mechanism via attenuating the inflammatory response in NMRs. Our study sheds light on the importance of a dampened inflammatory response as a non-cell-autonomous cancer resistance mechanism in NMRs.

A pair of ascending neurons in the subesophageal zone mediates aversive sensory inputs-evoked backward locomotion in Drosophila larvae.

Animals typically avoid unwanted situations with stereotyped escape behavior. For instance, Drosophila larvae often escape from aversive stimuli to the head, such as mechanical stimuli and blue light irradiation, by backward locomotion. Responses to these aversive stimuli are mediated by a variety of sensory neurons including mechanosensory class III da (C3da) sensory neurons and blue-light responsive class IV da (C4da) sensory neurons and Bolwig's organ (BO). How these distinct sensory pathways evoke backward locomotion at the circuit level is still incompletely understood. Here we show that a pair of cholinergic neurons in the subesophageal zone, designated AMBs, evoke robust backward locomotion upon optogenetic activation. Anatomical and functional analysis shows that AMBs act upstream of MDNs, the command-like neurons for backward locomotion. Further functional analysis indicates that AMBs preferentially convey aversive blue light information from C4da neurons to MDNs to elicit backward locomotion, whereas aversive information from BO converges on MDNs through AMB-independent pathways. We also found that, unlike in adult flies, MDNs are dispensable for the dead end-evoked backward locomotion in larvae. Our findings thus reveal the neural circuits by which two distinct blue light-sensing pathways converge on the command-like neurons to evoke robust backward locomotion, and suggest that distinct but partially redundant neural circuits including the command-like neurons might be utilized to drive backward locomotion in response to different sensory stimuli as well as in adults and larvae.

DBS is activated by EPHB2/SRC signaling-mediated tyrosine phosphorylation in HEK293 cells.

It is well known that Rho family small GTPases (Rho GTPase) has a role of molecular switch in intracellular signal transduction. The switch cycle between GTP-bound and GDP-bound state of Rho GTPase regulates various cell responses such as gene transcription, cytoskeletal rearrangements, and vesicular trafficking. Rho GTPase-specific guanine nucleotide exchange factors (RhoGEFs) are regulated by various extracellular stimuli and activates Rho GTPase such as RhoA, Rac1, and Cdc42. The molecular mechanisms that regulate RhoGEFs are poorly understood. Our studies reveal that Dbl's big sister (DBS), a RhoGEF for Cdc42 and RhoA, is phosphorylated at least on tyrosine residues at 479, 660, 727, and 926 upon stimulation by SRC signaling and that the phosphorylation at Tyr-660 is particularly critical for the serum response factor (SRF)-dependent transcriptional activation of DBS by Ephrin type-B receptor 2 (EPHB2)/SRC signaling. In addition, our studies also reveal that the phosphorylation of Tyr-479 and Tyr-660 on DBS leads to the actin cytoskeletal reorganization by EPHB2/SRC signaling. These findings are thought to be useful for understanding pathological conditions related to DBS such as cancer and non-syndromic autism in future.

Insulin-like growth factor 1 regulation of proliferation and differentiation of Xenopus laevis myogenic cells in vitro.

To understand the mechanism of muscle remodeling during Xenopus laevis metamorphosis, we examined the in vitro effect of insulin-like growth factor 1 (IGF-1) on growth and differentiation of three different-fate myogenic cell populations: tadpole tail, tadpole dorsal, and young adult leg muscle. IGF-1 promoted growth and differentiation of both tail and leg myogenic cells only under conditions where these cells could proliferate. Inhibition of cell proliferation by DNA synthesis inhibitor cytosine arabinoside completely canceled the IGF-1's cell differentiation promotion, suggesting the possibility that IGF-1's differentiation-promotion effect is an indirect effect via IGF-1's cell proliferation promotion. IGF-1 promoted differentiation dose dependently with maximum effect at 100-500 ng/ml. RT-PCR analysis revealed the upregulation (11-fold) of ifg1 mRNA expression in developing limbs, suggesting that IGF-1 plays a role in promoting muscle differentiation during limb development. The combined effect of triiodo-L-thyronine (T3) and IGF-1 was also examined. In adult leg cells, IGF-1 promoted growth and differentiation irrespective of the presence of T3. In larval tail cells, cell count was 76% lower in the presence of T3, and IGF-1 did not promote proliferation and differentiation in T3-containing medium. In larval dorsal cells, cell count was also lower in the presence of T3, but IGF-1 enhanced proliferation and differentiation in T3-containing medium. This result is likely due to the presence among dorsal cells of both adult and larval types (1:1). Thus, IGF-1 affects only adult-type myogenic cells in the presence of T3 and helps accelerate dorsal muscle remodeling during metamorphosis.

Adult Drosophila sensory neurons specify dendritic territories independently of dendritic contacts through the Wnt5-Drl signaling pathway.

Sensory neurons with common functions are often nonrandomly arranged and form dendritic territories in stereotypic spatial patterns throughout the nervous system, yet molecular mechanisms of how neurons specify dendritic territories remain largely unknown. In Drosophila larvae, dendrites of class IV sensory (C4da) neurons completely but nonredundantly cover the whole epidermis, and the boundaries of these tiled dendritic fields are specified through repulsive interactions between homotypic dendrites. Here we report that, unlike the larval C4da neurons, adult C4da neurons rely on both dendritic repulsive interactions and external positional cues to delimit the boundaries of their dendritic fields. We identify Wnt5 derived from sternites, the ventral-most part of the adult abdominal epidermis, as the critical determinant for the ventral boundaries. Further genetic data indicate that Wnt5 promotes dendrite termination on the periphery of sternites through the Ryk receptor family kinase Derailed (Drl) and the Rho GTPase guanine nucleotide exchange factor Trio in C4da neurons. Our findings thus uncover the dendritic contact-independent mechanism that is required for dendritic boundary specification and suggest that combinatory actions of the dendritic contact-dependent and -independent mechanisms may ensure appropriate dendritic territories of a given neuron.