Modulation of CP2 Family Transcriptional Activity by CRTR-1 and Sumoylation

CRTR-1 is a member of the CP2 family of transcription factors. Unlike other members of the family which are widely expressed, CRTR-1 expression shows specific spatio-temporal regulation. Gene targeting demonstrates that CRTR-1 plays a central role in the maturation and function of the salivary glands and the kidney. CRTR-1 has also recently been identified as a component of the complex transcriptional network that maintains pluripotency in embryonic stem (ES) cells. CRTR-1 was previously shown to be a repressor of transcription. We examine the activity of CRTR-1 in ES and other cells and show that CRTR-1 is generally an activator of transcription and that it modulates the activity of other family members, CP2, NF2d9 and altNF2d9, in a cell specific manner. We also demonstrate that CRTR-1 activity is regulated by sumoylation at a single major site, residue K30. These findings imply that functional redundancy with other family members may mask important roles for CRTR-1 in other tissues, including the blastocyst stage embryo and embryonic stem cells

The scaffold protein KSR1, a novel therapeutic target for the treatment of Merlin-deficient tumors

Merlin has broad tumor-suppressor functions as its mutations have been identified in multiple benign tumors and malignant cancers. In all schwannomas, the majority of meningiomas and 1/3 of ependymomas Merlin loss is causative. In neurofibromatosis type 2, a dominantly inherited tumor disease because of the loss of Merlin, patients suffer from multiple nervous system tumors and die on average around age 40. Chemotherapy is not effective and tumor localization and multiplicity make surgery and radiosurgery challenging and morbidity is often considerable. Thus, a new therapeutic approach is needed for these tumors. Using a primary human in vitro model for Merlin-deficient tumors, we report that the Ras/Raf/mitogen-activated protein, extracellular signal-regulated kinase kinase (MEK)/extracellular signal-regulated kinase (ERK) scaffold, kinase suppressor of Ras 1 (KSR1), has a vital role in promoting schwannomas development. We show that KSR1 overexpression is involved in many pathological phenotypes caused by Merlin loss, namely multipolar morphology, enhanced cell-matrix adhesion, focal adhesion and, most importantly, increased proliferation and survival. Our data demonstrate that KSR1 has a wider role than MEK1/2 in the development of schwannomas because adhesion is more dependent on KSR1 than MEK1/2. Immunoprecipitation analysis reveals that KSR1 is a novel binding partner of Merlin, which suppresses KSR1's function by inhibiting the binding between KSR1 and c-Raf. Our proteomic analysis also demonstrates that KSR1 interacts with several Merlin downstream effectors, including E3 ubiquitin ligase CRL4DCAF1. Further functional studies suggests that KSR1 and DCAF1 may co-operate to regulate schwannomas formation. Taken together, these findings suggest that KSR1 serves as a potential therapeutic target for Merlin-deficient tumors

Mechanisms of T cell organotropism

F.M.M.-B. is supported by the British Heart Foundation, the Medical Research Council of the UK and the Gates Foundation

Childhood trauma, life-time self-harm, and suicidal behaviour and ideation are associated with polygenic scores for autism

Abstract: Autistic individuals experience significantly elevated rates of childhood trauma, self-harm and suicidal behaviour and ideation (SSBI). Is this purely the result of negative environmental experiences, or does this interact with genetic predisposition? In this study we investigated if a genetic predisposition for autism is associated with childhood trauma using polygenic scores (PGS) and genetic correlations in the UK Biobank (105,222 < N < 105,638), and tested potential mediators and moderators of the association between autism, childhood trauma and SSBI. Autism PGS were significantly associated with childhood trauma (max R2 = 0.096%, P < 2 × 10−16), self-harm ideation (max R2 = 0.108%, P < 2 × 10−16), and self-harm (max R2 = 0.13%, P < 2 × 10−16). Supporting this, we identified significant genetic correlations between autism and childhood trauma (rg = 0.36 ± 0.05, P = 8.13 × 10−11), self-harm ideation (rg = 0.49 ± 0.05, P = 4.17 × 10−21) and self-harm (rg = 0.48 ± 0.05, P = 4.58 × 10−21), and an over-transmission of PGS for the two SSBI phenotypes from parents to autistic probands. Male sex negatively moderated the effect of autism PGS on childhood trauma (β = −0.023 ± 0.005, P = 6.74 × 10−5). Further, childhood trauma positively moderated the effect of autism PGS on self-harm score (β = 8.37 × 10−3 ± 2.76 × 10−3, P = 2.42 × 10−3) and self-harm ideation (β = 7.47 × 10−3 ± 2.76 × 10−3, P = 6.71 × 10−3). Finally, depressive symptoms, quality and frequency of social interactions, and educational attainment were significant mediators of the effect of autism PGS on SSBI, with the proportion of effect mediated ranging from 0.23 (95% CI: 0.09–0.32) for depression to 0.008 (95% CI: 0.004–0.01) for educational attainment. Our findings identify that a genetic predisposition for autism is associated with adverse life-time outcomes, which represent complex gene-environment interactions, and prioritizes potential mediators and moderators of this shared biology. It is important to identify sources of trauma for autistic individuals in order to reduce their occurrence and impact

Efficient age determination: how freezing affects eye lens weight of the small rodent species Arvicola terrestris

Age determination of animals by measuring the weight of their eye lenses is a widely used method in wildlife biology. In general, it is recommended to prepare lenses immediately after trapping to avoid errors in the age estimation due to decomposition of lens tissue. However, in many field studies, large numbers of animals need to be trapped over long periods of time in huge areas and by many different field workers. Therefore, the immediate preparation of eye lenses imposes a considerable logistic constraint that could be avoided by prior freezing of trapped animals. To assess the impact of freezing, weights of lens of frozen and unfrozen eyes of 114 Arvicola terrestris were compared pair wise. The frozen lenses weighed at average 3.3% (95% CI: 2.4–4.1%) more than the unfrozen ones from the same animals. Freezing time, weight of lenses and mean temperature of the trapping day as an indicator of decomposition speed did not affect the freezing-induced weight increase. Age estimates based on weights of unfrozen lenses varied between 24 and 445 days. Estimates based on frozen lenses were systematically higher. Applying a constant correction factor of 1.033−1 for the weight of frozen lenses corrects this overestimation of age. We conclude that age determination with frozen lenses of small rodents can yield valid age estimates if a correction factor for freezing is applied. Thus, age determination can be organised much more efficiently in field studies, which is highly advantageous for many ecological, agricultural and epidemiological research projects