Explore the vast range of titles available.

The cellular interactions controlling digit numbers and identities have remained largely elusive. Here, we leverage the anterior digit and identity loss in Grem1 tetradactyl mouse limb buds to identify early specified limb bud mesenchymal progenitor (LMP) populations whose size and distribution is governed by spatial modulation of BMP activity and SHH signaling. D istal-autopodial LMPs (dLMP) express signature genes required for autopod and digit development, and alterations affecting the dLMP population size prefigure the changes in digit numbers that characterize specific congenital malformations. A second, p eripheral LMP (pLMP) population is anteriorly biased and reduction/loss of its asymmetric distribution underlies the loss of middle digit asymmetry and identities in Grem1 tetradactyl and pig limb buds. pLMPs depend on BMP activity, while dLMPs require GREM1-mediated BMP antagonism. Taken together, the spatial alterations in GREM1 antagonism in mouse mutant and evolutionarily diversified pig limb buds tunes BMP activity, which impacts dLMP and pLMP populations in an opposing manner. The initial cellular alterations underlying changes in digit numbers and identities were unknown. Here, Palacio et al. identify two limb bud progenitor populations that are impacted in an opposing manner by changes in BMP antagonism linked to congenital and evolutionary digit variations.

A lingering question in developmental biology has centered on how transcription factors with widespread distribution in vertebrate embryos can perform tissue-specific functions. Here, using the murine hindlimb as a model, we investigate the elusive mechanisms whereby PBX TALE homeoproteins, viewed primarily as HOX cofactors, attain context-specific developmental roles despite ubiquitous presence in the embryo. We first demonstrate that mesenchymal-specific loss of PBX1/2 or the transcriptional regulator HAND2 generates similar limb phenotypes. By combining tissue-specific and temporally controlled mutagenesis with multi-omics approaches, we reconstruct a gene regulatory network (GRN) at organismal-level resolution that is collaboratively directed by PBX1/2 and HAND2 interactions in subsets of posterior hindlimb mesenchymal cells. Genome-wide profiling of PBX1 binding across multiple embryonic tissues further reveals that HAND2 interacts with subsets of PBX-bound regions to regulate limb-specific GRNs. Our research elucidates fundamental principles by which promiscuous transcription factors cooperate with cofactors that display domain-restricted localization to instruct tissue-specific developmental programs. Many key developmental transcriptional regulators are broadly expressed but perform distinct functions in specific tissues. Here they show that ubiquitously expressed PBX factors gain limb bud functionality by interaction with HAND2, uncovering fundamental principles of cooperation between promiscuous and tissue-specific regulators to instruct developmental programs.

Exon skipping mutations of the MET receptor tyrosine kinase (METex14), increasingly reported in cancers, occur in 3–4% of non–small‐cell lung cancer (NSCLC). Only 50% of patients have a beneficial response to treatment with MET‐tyrosine kinase inhibitors (TKIs), underlying the need to understand the mechanism of METex14 oncogenicity and sensitivity to TKIs. Whether METex14 is a driver mutation and whether it requires hepatocyte growth factor (HGF) for its oncogenicity in a range of in vitro functions and in vivo has not been fully elucidated from previous preclinical models. Using CRISPR/Cas9, we developed a METex14/WT isogenic model in nontransformed human lung cells and report that the METex14 single alteration was sufficient to drive MET‐dependent in vitro anchorage‐independent survival and motility and in vivo tumorigenesis, sensitising tumours to MET‐TKIs. However, we also show that human HGF (hHGF) is required, as demonstrated in vivo using a humanised HGF knock‐in strain of mice and further detected in tumour cells of METex14 NSCLC patient samples. Our results also suggest that METex14 oncogenicity is not a consequence of an escape from degradation in our cell model. Thus, we developed a valuable model for preclinical studies and present results that have potential clinical implication.

BackgroundRecent evidence showed that 50% of chronic obstructive pulmonary disease (COPD) may be attributable to air pollution. We aimed to investigate the association between long-term air pollution exposure and COPD symptoms/diagnosis in an Italian epidemiological study.MethodsA total of 14 420 adults living in Ancona, Pavia, Pisa, Sassari, Turin and Verona were investigated in 2005–2011. Data on risk factors and health outcomes were collected by questionnaires; mean annual concentrations of particulate matters (PM) like PM10 and PM2.5 as well as NO2 and mean summer concentrations of O3 (µg/m3) at residential level with a 1 km resolution (period 2013–2015) were obtained by machine learning techniques. The relationship of pollutant exposure and COPD prevalence was assessed by logistic regression models (single pollutant) and principal component logistic regression models (multipollutant) adjusting for sex, age, education level, smoking habits, season of interview, and city-specific climatic index and including a random intercept for cohorts.ResultsA 10 µg/m3 increase of PM10, PM2.5 and NO2 exposure was related to COPD diagnosis and symptoms (OR 1.31, 95% CI 1.03 to 1.65 for PM2.5; OR 1.26, 95% CI 1.03 to 1.54 for PM10 and OR 1.07, 95% CI 1.00 to 1.15 for NO2) using a multipollutant approach. Similar results emerged for dyspnoea (OR 1.24, 95% CI 1.05 to 1.47 for PM2.5; OR 1.21, 95% CI 1.05 to 1.39 for PM10 and OR 1.06, 95% CI 1.01 to 1.11 for NO2). Associations between COPD symptoms and summer O3 were less clear. By multipollutant models, OR estimates were lower than those by single pollutant models.ConclusionsFurther evidence about the relationship between air pollution and respiratory effects in Italian adults was provided indicating PM as the main driver.

The human ether‐à‐go‐go‐related gene (hERG)1 K+ channel is upregulated in human colorectal cancer cells and primary samples. In this study, we examined the role of hERG1 in colorectal carcinogenesis using two mouse models: adenomatous polyposis coli (Apcmin/+) and azoxymethane (AOM)‐treated mice. Colonic polyps of Apcmin/+ mice overexpressed mERG1 and their formation was reverted by the hERG1 blocker E4031. AOM was applied to either hERG1‐transgenic (TG) mice, which overexpress hERG1 in the mucosa of the large intestine, or wild‐type mice. A significant increase of both mucin‐depleted foci and polyps in the colon of hERG1‐TG mice was detected. Both the intestine of TG mice and colonic polyps of Apcmin/+ showed an upregulation of phospho‐Protein Kinase B (pAkt)/vascular endothelial growth factor (VEGF‐A) and an increased angiogenesis, which were reverted by treatment with E4031. On the whole, this article assigns a relevant role to hERG1 in the process of in vivo colorectal carcinogenesis. We studied the role of hERG1 in colorectal carcinogenesis using Apcmin/+ and azoxymethane (AOM)‐treated mice as models. In Apcmin/+ mice, the development of colonic polyps, shown to overexpress hERG1, was reverted by hERG1 blockers. AOM triggered a higher number of preneoplastic lesions such as mucin‐depleted foci and polyps in the colon of transgenic mice, which overexpress hERG1, compared to wild‐type mice. In either model, a hERG1‐dependent increase of both VEGF‐A and angiogenesis was detected.

The cellular mechanisms controlling digit numbers and identities have remained elusive. Profiling of wild-type (pentadactyl) and Grem1 tetradactyl mouse limb buds identifies cellular changes affecting two limb bud mesenchymal progenitor (LMP) populations. In mutant limb buds, the anteriorly biased distribution of peripheral LMPs (pLMPs) is lost and the population expanded, while the distal-posterior LMP (dLMP) population is reduced from early stages onward. Analysis of LMP signature genes in wildtype and mutant mouse limb buds with digit loss or gain establishes that pLMPs are positively regulated by BMP signaling, while dLMPs require GREM1-mediated BMP antagonism. dLMPs encompass digit progenitors and altering their population size prefigures changes in digit numbers. The anteriorly biased pLMP distribution is linked to digit asymmetry as loss of this bias in tetradactyl mouse and pig limb buds underlies middle digit symmetry and identity loss. This study indicates that variable spatial Grem1 expression in mutant and evolutionary diversified limb buds tunes BMP activity, impacting both LMP populations in a complementary manner.

Self-organization, such as the emergence of a pattern from a homogenous state, is a fascinating property of biological systems. Early limb bud outgrowth and patterning in mice are controlled by a robust and self-regulatory signaling system, and initiation of the periodic digit-interdigit pattern appears under control of a self-regulatory Turing system. Previous studies established the requirement of WNT and BMP signaling for both early limb bud and digit-interdigit morphogenesis, but the molecular changes underlying the transition from early limb bud signaling to the digit-interdigit patterning system remained unknown. Here, we use small molecule inhibitors to rapidly but transiently block WNT signaling to identify the early transcriptional targets that are altered during disruption and recovery of limb bud and digit development. Together, this study highlights the overarching role of WNT signaling in controlling early limb bud outgrowth and patterning, and establishment of the periodic digit-interdigit pattern. Finally, the transient WNT signaling disruption approach reveals the plasticity and robustness of these self-organizing limb bud and digit patterning systems.Competing Interest StatementThe authors have declared no competing interest.