Generation of rat lungs by blastocyst complementation in Fgfr2b-deficient mouse model

Regenerative medicine is a tool to compensate for the shortage of lungs for transplantation, but it remains difficult to construct a lung in vitro due to the complex three-dimensional structures and multiple cell types required. A blastocyst complementation method using interspecies chimeric animals has been attracting attention as a way to create complex organs in animals, but successful lung formation has not yet been achieved. Here, we applied a reverse-blastocyst complementation method to clarify the conditions required to form lungs in an Fgfr2b-deficient mouse model. We then successfully formed a rat-derived lung in the mouse model without generating a mouse line by applying a tetraploid-based organ-complementation method. Importantly, rat lung epithelial cells retained their developmental timing even in the mouse body. This result provides useful insights regarding the need to overcome the barrier of species-specific developmental timing in order to generate functional lungs in interspecies chimeras.

A longitudinal study examining the associations between interpersonal trauma and romantic relationships among college students

We examined the associations between the developmental timing of interpersonal trauma exposure (IPT) and three indicators of involvement in and quality of romantic relationships in emerging adulthood: relationship status, relationship satisfaction, and partner alcohol use. We further examined whether these associations varied in a sex-specific manner. In a sample of emerging adult college students (N = 12,358; 61.5% female) assessed longitudinally across the college years, we found precollege IPT increased the likelihood of being in a relationship, while college-onset IPT decreased the likelihood. Precollege and college-onset IPT predicted lower relationship satisfaction, and college-onset IPT predicted higher partner alcohol use. There was no evidence that associations between IPT and relationship characteristics varied in a sex-specific manner. Findings indicate that IPT exposure, and the developmental timing of IPT, may affect college students’ relationship status. Findings also suggest that IPT affects their ability to form satisfying relationships with prosocial partners.

Experiences of adversity in childhood and adolescence and cortisol in late adolescence

Early life adversity influences the diurnal cortisol rhythm, yet the relative influence of different characteristics of adversity remains unknown. In this study, we examine how developmental timing (childhood vs. adolescence), severity (major vs. minor), and domain of early life adversity relate to diurnal cortisol rhythms in late adolescence. We assessed adversity retrospectively in early adulthood in a subsample of 236 participants from a longitudinal study of a diverse community sample of suburban adolescents oversampled for high neuroticism. We used multilevel modeling to assess associations between our adversity measures and the diurnal cortisol rhythm (waking and bedtime cortisol, awakening response, slope, and average cortisol). Major childhood adversities were associated with flatter daily slope, and minor adolescent adversities were associated with greater average daily cortisol. Examining domains of childhood adversities, major neglect and sexual abuse were associated with flatter slope and lower waking cortisol, with sexual abuse also associated with higher cortisol awakening response. Major physical abuse was associated with higher waking cortisol. Among adolescent adversities domains, minor neglect, emotional abuse, and witnessing violence were associated with greater average cortisol. These results suggest severity, developmental timing, and domain of adversity influence the association of early life adversity with stress response system functioning.

Oncogenic and Tumor Suppressor Functions for Lymphoid Enhancer Factor 1 in a Murine Model of T Acute Lymphoblastic Leukemia

T lymphocyte acute lymphoblastic leukemia (T-ALL) is a heterogeneous disease affecting T cells at multiple stages of their development and is characterized by frequent genomic alterations. The transcription factor LEF1 is inactivated through mutation in a subset of T-ALL cases but elevated LEF1 expression and activating mutations have also been identified in this disease. Here we show, in a murine model of T-ALL, that the developmental timing of Lef1 mutation impacts its ability to function as a cooperative tumor suppressor or oncogene. T cell transformation in the presence of LEF1 allows leukemic cells to become addicted to its presence. In contrast, deletion prior to transformation both accelerates leukemogenesis and results in leukemic cells with altered expression of genes controlling receptor signaling pathways. Our data demonstrate that the developmental timing of Lef1 mutations impact its apparent oncogenic or tumor suppressive characteristics and demonstrate the utility of mouse models for understanding the cooperation and consequence of mutational order in leukemogenesis.

BLMP-1 promotes developmental cell death in C. elegans by timely repression of ced-9/bcl-2 transcription

Programmed cell death (PCD) is a common cell fate in metazoan development. PCD effectors are extensively studied, but how they are temporally regulated is less understood. Here we report a mechanism controlling tail-spike cell death onset during C. elegans development. We show that the Zn-finger transcription factor BLMP-1/Blimp1, which controls larval development timing, also regulates embryonic tail-spike cell death initiation. BLMP-1 functions upstream of CED-9/BCL-2 and in parallel to DRE-1/FBXO11, another CED-9 and tail-spike cell death regulator. BLMP-1 expression is detected in the tail-spike cell shortly after the cell is born, and blmp-1 mutations promote ced-9-dependent tail-spike cell survival. BLMP-1 binds ced-9/bcl-2 gene regulatory sequences, and inhibits ced-9 transcription just before cell-death onset. BLMP-1 and DRE-1 function together to regulate developmental timing, and their mammalian homologs regulate B-lymphocyte fate. Our results, therefore, identify roles for developmental timing genes in cell-death initiation, and suggest conservation of these functions.

Multivariate analysis of morphology, behaviour, growth and developmental timing in hybrids brings new insights into the divergence of sympatric Arctic charr morphs

Background Studying the development of fitness related traits in hybrids from populations diverging in sympatry is a fundamental approach to understand the processes of speciation. However, such traits are often affected by covariance structures that complicate the comprehension of these processes, especially because the interactive relationships between traits of different nature (e.g. morphology, behaviour, life-history) remain largely unknown in this context. In a common garden setup, we conducted an extensive examination of a large suit of traits putatively involved in the divergence of two morphs of Arctic charr (Salvelinus alpinus), and investigated the consequences of potential patterns of trait covariance on the phenotype of their hybrids. These traits were measured along ontogeny and involved growth, yolk sac resorption, developmental timing (hatching and the onset of exogeneous feeding), head morphology and feeding behaviour. Results Growth trajectories provided the strongest signal of phenotypic divergence between the two charr. Strikingly, the first-generation hybrids did not show intermediate nor delayed growth but were similar to the smallest morph, suggesting parental biases in the inheritance of growth patterns. However, we did not observe extensive multivariate trait differences between the two morphs and their hybrids. Growth was linked to head morphology (suggesting that morphological variations in early juveniles relate to simple allometric effects) but this was the only strong signal of covariance observed between all the measured traits. Furthermore, we did not report evidence for differences in overall phenotypic variance between morphs, nor for enhanced phenotypic variability in their hybrids. Conclusion Our study shed light on the multivariate aspect of development in a context of adaptive divergence. The lack of evidence for the integration of most traits into a single covariance structure suggested that phenotypic constraints may not always favour nor impede divergence toward ecological niches differing in numerous physical and ecological variables, as observed in the respective habitats of the two charr. Likewise, the role of hybridization as a disruptive agent of trait covariance may not necessarily be significant in the evolution of populations undergoing resource polymorphism.