Integration of Nodal and BMP Signals in the Heart Requires FoxH1 to Create Left–Right Differences in Cell Migration Rates That Direct Cardiac Asymmetry

Failure to properly establish the left–right (L/R) axis is a major cause of congenital heart defects in humans, but how L/R patterning of the embryo leads to asymmetric cardiac morphogenesis is still unclear. We find that asymmetric Nodal signaling on the left and Bmp signaling act in parallel to establish zebrafish cardiac laterality by modulating cell migration velocities across the L/R axis. Moreover, we demonstrate that Nodal plays the crucial role in generating asymmetry in the heart and that Bmp signaling via Bmp4 is dispensable in the presence of asymmetric Nodal signaling. In addition, we identify a previously unappreciated role for the Nodal-transcription factor FoxH1 in mediating cell responsiveness to Bmp, further linking the control of these two pathways in the heart. The interplay between these TGFβ pathways is complex, with Nodal signaling potentially acting to limit the response to Bmp pathway activation and the dosage of Bmp signals being critical to limit migration rates. These findings have implications for understanding the complex genetic interactions that lead to congenital heart disease in humans

DYX1C1 is required for axonemal dynein assembly and ciliary motility

Dyx1c1 has been associated with dyslexia and neuronal migration in the developing neocortex. Unexpectedly, we found that deletion of Dyx1c1 exons 2–4 in mice caused a phenotype resembling primary ciliary dyskinesia (PCD), a genetically heterogeneous disorder characterized by chronic airway disease, laterality defects, and male infertility. This phenotype was confirmed independently in mice with a Dyx1c1c.T2A start codon mutation recovered from an ENU mutagenesis screen. Morpholinos targeting dyx1c1 in zebrafish also created laterality and ciliary motility defects. In humans, recessive loss-of-function DYX1C1 mutations were identified in twelve PCD individuals. Ultrastructural and immunofluorescence analyses of DYX1C1-mutant motile cilia in mice and humans revealed disruptions of outer and inner dynein arms (ODA/IDA). DYX1C1 localizes to the cytoplasm of respiratory epithelial cells, its interactome is enriched for molecular chaperones, and it interacts with the cytoplasmic ODA/IDA assembly factor DNAAF2/KTU. Thus, we propose that DYX1C1 is a newly identified dynein axonemal assembly factor (DNAAF4)

Sc65-Null Mice Provide Evidence for a Novel Endoplasmic Reticulum Complex Regulating Collagen Lysyl Hydroxylation

Collagen is a major component of the extracellular matrix and its integrity is essential for connective tissue and organ function. The importance of proteins involved in intracellular collagen post-translational modification, folding and transport was recently highlighted from studies on recessive forms of osteogenesis imperfecta (OI). Here we describe the critical role of SC65 (Synaptonemal Complex 65, P3H4), a leprecan-family member, as part of an endoplasmic reticulum (ER) complex with prolyl 3-hydroxylase 3. This complex affects the activity of lysyl-hydroxylase 1 potentially through interactions with the enzyme and/or cyclophilin B. Loss of Sc65 in the mouse results in instability of this complex, altered collagen lysine hydroxylation and cross-linking leading to connective tissue defects that include low bone mass and skin fragility. This is the first indication of a prolyl-hydroxylase complex in the ER controlling lysyl-hydroxylase activity during collagen synthesis

Influence of hydraulic property correlation on predicted dense nonaqueous phase liquid source zone architecture, mass recovery and contaminant flux

Peer Reviewedhttp://deepblue.lib.umich.edu/bitstream/2027.42/94685/1/wrcr9972.pd

Role of the Gut Endoderm in Relaying Left-Right Patterning in Mice

Analysis of Sox17 mutant mice reveals that gap junction coupling across the gut endoderm of the embryo transmits the left-right asymmetric signal from the node to the site of asymmetric organogenesis in mice

Fundamental Neutron Physics: a White Paper on Progress and Prospects in the US

Fundamental neutron physics, combining precision measurements and theory, probes particle physics at short range with reach well beyond the highest energies probed by the LHC. Significant US efforts are underway that will probe BSM CP violation with orders of magnitude more sensitivity, provide new data on the Cabibbo anomaly, more precisely measure the neutron lifetime and decay, and explore hadronic parity violation. World-leading results from the US Fundamental Neutron Physics community since the last Long Range Plan, include the world's most precise measurement of the neutron lifetime from UCN$\tau$, the final results on the beta-asymmetry from UCNA and new results on hadronic parity violation from the NPDGamma and n-${^3}$He runs at the FNPB (Fundamental Neutron Physics Beamline), precision measurement of the radiative neutron decay mode and n-${}^4$He at NIST. US leadership and discovery potential are ensured by the development of new high-impact experiments including BL3, Nab, LANL nEDM and nEDM@SNS. On the theory side, the last few years have seen results for the neutron EDM from the QCD $\theta$ term, a factor of two reduction in the uncertainty for inner radiative corrections in beta-decay which impacts CKM unitarity, and progress on {\it ab initio} calculations of nuclear structure for medium-mass and heavy nuclei which can eventually improve the connection between nuclear and nucleon EDMs. In order to maintain this exciting program and capitalize on past investments while also pursuing new ideas and building US leadership in new areas, the Fundamental Neutron Physics community has identified a number of priorities and opportunities for our sub-field covering the time-frame of the last Long Range Plan (LRP) under development. This white paper elaborates on these priorities.Comment: arXiv admin note: text overlap with arXiv:2304.0345