The genetic basis of neurocranial size and shape across varied lab mouse populations.

Brain and skull tissues interact through molecular signalling and mechanical forces during head development, leading to a strong correlation between the neurocranium and the external brain surface. Therefore, when brain tissue is unavailable, neurocranial endocasts are often used to approximate brain size and shape. Evolutionary changes in brain morphology may have resulted in secondary changes to neurocranial morphology, but the developmental and genetic processes underlying this relationship are not well understood. Using automated phenotyping methods, we quantified the genetic basis of endocast variation across large genetically varied populations of laboratory mice in two ways: (1) to determine the contributions of various genetic factors to neurocranial form and (2) to help clarify whether a neurocranial variation is based on genetic variation that primarily impacts bone development or on genetic variation that primarily impacts brain development, leading to secondary changes in bone morphology. Our results indicate that endocast size is highly heritable and is primarily determined by additive genetic factors. In addition, a non-additive inbreeding effect led to founder strains with lower neurocranial size, but relatively large brains compared to skull size; suggesting stronger canalization of brain size and/or a general allometric effect. Within an outbred sample of mice, we identified a locus on mouse chromosome 1 that is significantly associated with variation in several positively correlated endocast size measures. Because the protein-coding genes at this locus have been previously associated with brain development and not with bone development, we propose that genetic variation at this locus leads primarily to variation in brain volume that secondarily leads to changes in neurocranial globularity. We identify a strain-specific missense mutation within Akt3 that is a strong causal candidate for this genetic effect. Whilst it is not appropriate to generalize our hypothesis for this single locus to all other loci that also contribute to the complex trait of neurocranial skull morphology, our results further reveal the genetic basis of neurocranial variation and highlight the importance of the mechanical influence of brain growth in determining skull morphology.

MicroRNA miR-145-5p inhibits Phospholipase D 5 (PLD5) to downregulate cell proliferation and metastasis to mitigate prostate cancer.

Prostate cancer (PCa), a frequently detected malignant tumor, is the fifth leading global cancer mortality cause in men. Although research has improved the PCa survival rate, significantly reduced survival occurs among patients at the metastatic stage. MiRNAs, which are short non-coding proteins, are crucial for several biological roles, essential for PCa proliferation, differentiation, multiplication, and migration. The investigation aimed to explore miR-145-5p and PLD5 association and clarify their function in regulating proliferation in PCa cell lines.The study used PC-3, LNCaP, DU-145 PCa, and RWPE-1 non-cancerous cell line, PCa, and BPH tissue specimens, and nude mice to validate results. MiR-145-5p and PLD5 manifestation were assessed through RT-qPCR. PLD5 and miR-145 binding was determined through dual-luciferase reporter gene assays. Validation of cell proliferation, migration, and invasion was assessed through MTT, scratch wound, and transwell assays, respectively.The results indicated a downregulation of miR-145-5p level in PCa cell lines and tissues in comparison to the non-cancerous controls. PLD5 overexpression exerted a cancerous effect while mimicking of miR-145-5p reversed the PLD5-oncogenic effects and significantly inhibited PCa cells proliferation, migration, invasion, and metastasis.In conclusion, the study revealed that miR-145-5p upregulated apoptosis and repressed migration, invasion, and metastasis of PCa via direct PLD5 modulation.

Fine mapping of the uterine leiomyoma locus on 1q43 close to a lncRNA in the RGS7-FH interval.

Mutations in fumarate hydratase (FH) on chromosome 1q43 cause a rare cancer syndrome, hereditary leiomyomatosis and renal cell cancer (HLRCC), but are rare in nonsyndromic and common uterine leiomyoma (UL) or fibroids. Studies suggested that variants in FH or in a linked gene may also predispose to UL. We re-sequenced 2.3 Mb of DNA spanning FH in 96 UL cases and controls from the multiethnic NIEHS-uterine fibroid study, and in 18 HLRCC-associated UL probands from European families then selected 221 informative SNPs for follow-up genotyping. We report promising susceptibility associations with UL peaking at rs78220092 (P=7.0×10(-5)) in the RGS7-FH interval in African Americans. In race-combined analyses and in meta-analyses (n=916), we identified promising associations with risk peaking upstream of a non-protein coding RNA (lncRNA) locus located in the RGS7-FH interval closer to RGS7, and associations with tumor size peaking in the distal phospholipase D family, member 5 (PLD5) gene at rs2654879 (P=1.7×10(-4)). We corroborated previously reported FH mutations in nine out of the 18 HLRCC-associated UL cases and identified two missense mutations in FH in only two nonsyndromic UL cases and one control. Our fine association mapping and integration of existing gene profiling data showing upregulated expression of the lncRNA and downregulation of PLD5 in fibroids, as compared to matched myometrium, suggest a potential role of this genomic region in UL pathogenesis. While the identified variations at 1q43 represent a potential risk locus for UL, future replication analyses are required to substantiate our observation.