Co-translational protein targeting facilitates centrosomal recruitment of PCNT during centrosome maturation in vertebrates.

As microtubule-organizing centers of animal cells, centrosomes guide the formation of the bipolar spindle that segregates chromosomes during mitosis. At mitosis onset, centrosomes maximize microtubule-organizing activity by rapidly expanding the pericentriolar material (PCM). This process is in part driven by the large PCM protein pericentrin (PCNT), as its level increases at the PCM and helps recruit additional PCM components. However, the mechanism underlying the timely centrosomal enrichment of PCNT remains unclear. Here, we show that PCNT is delivered co-translationally to centrosomes during early mitosis by cytoplasmic dynein, as evidenced by centrosomal enrichment of PCNT mRNA, its translation near centrosomes, and requirement of intact polysomes for PCNT mRNA localization. Additionally, the microtubule minus-end regulator, ASPM, is also targeted co-translationally to mitotic spindle poles. Together, these findings suggest that co-translational targeting of cytoplasmic proteins to specific subcellular destinations may be a generalized protein targeting mechanism

Immediate responses to ambient light in vivo reveal distinct subpopulations of suprachiasmatic VIP neurons

Summary: The circadian rhythm pacemaker, the suprachiasmatic nucleus (SCN), mediates light entrainment via vasoactive intestinal peptide (VIP) neurons (SCNVIP). Yet, how these neurons uniquely respond and connect to intrinsically photosensitive retinal ganglion cells (ipRGCs) expressing melanopsin (Opn4) has not been determined functionally in freely behaving animals. To address this, we first used monosynaptic tracing from SCNVIP neurons in mice and identified two SCNVIP subpopulations. Second, we recorded calcium changes in response to ambient light, at both bulk and single-cell levels, and found two unique activity patterns in response to high- and low-intensity blue light. The activity patterns of both subpopulations could be manipulated by application of an Opn4 antagonist. These results suggest that the two SCNVIP subpopulations connect to two types of Opn4-expressing ipRGCs, likely M1 and M2, but only one is responsive to red light. These findings have important implications for our basic understanding of non–image-forming circadian light processing

Release of endogenous dynorphin opioids in the prefrontal cortex disrupts cognition

Following repeated opioid use, some dependent individuals experience persistent cognitive deficits that contribute to relapse of drug-taking behaviors, and one component of this response may be mediated by the endogenous dynorphin/kappa opioid system in neocortex. In C57BL/6 male mice, we find that acute morphine withdrawal evokes dynorphin release in the medial prefrontal cortex (PFC) and disrupts cognitive function by activation of local kappa opioid receptors (KORs). Immunohistochemical analyses using a phospho-KOR antibody confirmed that both withdrawal-induced and optically evoked dynorphin release activated KOR in PFC. Using a genetically encoded sensor based on inert KOR (kLight1.2a), we revealed the in vivo dynamics of endogenous dynorphin release in the PFC. Local activation of KOR in PFC produced multi-phasic disruptions of memory processing in an operant-delayed alternation behavioral task, which manifest as reductions in response number and accuracy during early and late phases of an operant session. Local pretreatment in PFC with the selective KOR antagonist norbinaltorphimine (norBNI) blocked the disruptive effect of systemic KOR activation during both early and late phases of the session. The early, but not late phase disruption was blocked by viral excision of PFC KORs, suggesting an anatomically dissociable contribution of pre- and postsynaptic KORs. Naloxone-precipitated withdrawal in morphine-dependent mice or optical stimulation of pdynCre neurons using Channelrhodopsin-2 disrupted delayed alternation performance, and the dynorphin-induced effect was blocked by local norBNI. Our findings describe a mechanism for control of cortical function during opioid dependence and suggest that KOR antagonism could promote abstinence

Organ transplantation and skin cancer: basic problems and new perspectives

Solid organ transplant and subsequent graft survival have increased worldwide, while immunosuppression has prevented rejection with increasing success. Side effects of cutaneous infection and neoplasm, however, affect the majority of solid organ transplant recipients (OTRs). Squamous cell carcinoma of the skin (SCC) is the most common neoplasm overall following organ transplant with a risk that is 60-100 times greater than for the immunocompetent population. This review focuses on questions of ongoing debate about SCC formation in OTRs such as viral carcinogenesis, systemic photoprotection, photosensitization by drugs, the impact of immunosuppressive drugs and inflammation as a driver of carcinogenesis