Axial Patterning Research Articles

Multistep Algorithm to Predict RVOT PVC Site of Origin for Successful Ablation Using Available Criteria: A Two-Center Cross-Validation Study.

Predicting premature ventricular contraction (PVC) origin pre-ablation is a fundamental step, as right ventricular outflow tract (RVOT) PVC often leads to higher success rates. To compare nine published ECG criteria to differentiate between RVOT and non-RVOT origins of PVCs and develop a stepwise algorithm using those criteria to better determine PVC origin to predict ablation success. Two centers were involved in this study, the derivation group and the validation group. The derivation group included 65 patients with PVC left bundle branch block (LBBB) pattern morphology (predominantly negative in lead V1) and inferior axis (predominantly positive in leads II and III), who underwent ablation at Cipto Mangunkusumo Hospital (RSCM) (2017-2022). The validation group included 291 patients who underwent ablation at the Taipei Veteran General Hospital (2020-2023). We calculated and compared six diagnostic accuracy measures from nine previously published ECG morphology criteria to develop an algorithm to enhance the accuracy of predicting RVOT PVC origin for successful ablation. Our multistep algorithm using Criteria 5, 8, and 1 enhanced diagnostic performance compared to using each criterion alone. The accuracy, sensitivity, and specificity in the derivation group were 86.2%, 93.6%, and 66.7%, respectively; those in the validation group were 85.9%, 90.8%, and 64.7%, respectively. The ROC curve AUCs were 0.802 and 0.775, respectively. In cases of inferior axis and LBBB pattern PVCs, a multistep algorithm using multiple criteria increases the accuracy of predicting RVOT PVC origin instead of using a single criterion.

Predictors of Myocardial Fibrosis Detected by CMR in Patients With Idiopathic PVCs.

Premature ventricular contractions (PVCs) are a frequent electrocardiographic finding in routine medical practice, and 16% of the patients with idiopathic PVCs may have underlying heart disease. We analyzed the correlation between the morphology of the PVCs and the myocardial scarring identified by cardiac magnetic resonance (CMR), together with the impact of late gadolinium enhancement (LGE) on the need for ablation. Ninety-four patients (median age 56 years) with frequent PVCs (> 500 PVCs on 24 h) and a structurally normal heart were referred for comprehensive CMR. The patients were followed for 12 months. Patients were referred for ablation if they were symptomatic in the context of frequent PVCs. The prevalence of LGE identified by CMR was higher among males (OR 5.506 (2.092-14.49) p < 0.05), with an age ≥ 50 years (OR 1.047 (1.015-1.08), p < 0.05) and a higher PVC burden (OR 1.922 (1.723-1.976), p < 0.05). Additionally, patients with PVCs with a LBBB inferior axis had four times higher risk of exhibiting LGE (OR 4.09 (1.584-10.565), p < 0.05). In multivariate analysis, age (OR 1.059 (1.019-1.099), p < 0.05) and a LBBB inferior axis (OR 4.605 (1.472-14.404), p < 0.05) were independently associated with the presence of LGE. Patients with PVCs and apparently, structurally normal heart present myocardial scarring identified by CMR in 71.23% of cases. PVCs with LBBB inferior axis pattern, age ≥ 50 years and male sex are associated with the presence of LGE on CMR. In multivariate analysis, age and LBBB inferior axis were independently correlated with the presence of LGE.

Confinement Modulates Axial Patterning in Regenerating Hydra

The establishment of the body plan is a major step in animal morphogenesis. The role of mechanical forces and feedback in patterning the body plan remains unclear. Here we explore this question by studying regenerating Hydra tissues confined in narrow cylindrical channels, which constrain their morphology. We find that frustration between the orientation of the channel and the inherited axis in the regenerating tissues can lead to the formation of a multiaxial body plan. The morphological outcome is directly related to the pattern of nematic topological defects that emerges in the organization of the supracellular actomyosin fibers. When the inherited axis, which can be read out from the initial alignment of the supracellular fibers in the confined spheroid, is parallel to the channel's axis, the tissue regenerates normally into animals with a single body axis aligned with the channel. However, regenerating spheroids that are confined in a frustrated perpendicular configuration often develop excess defects (including negatively charged −1/2 defects) and regenerate into multiaxial morphologies. The influence of mechanical constraints on the regenerated body plan argues against an axial patterning mechanism that is based solely on inherited gradients of biochemical morphogens. We further show that the dependence of the regeneration outcomes on the initial tissue orientation can be recapitulated by a biophysical model, which considers the coupled dynamics of the nematic organization of the actomyosin fibers and a morphogen concentration field, incorporating a mechanochemical feedback loop involving strain-dependent morphogen production at defect sites. Published by the American Physical Society 2024

UHT Cow's Milk Supplementation Affects Cell Niches and Functions of the Gut-Brain Axis in BALB/c Mice.

Cow's milk is a bioactive cocktail with essential nutritional factors that is widely consumed during early childhood development. However, it has been associated with allergic responses and immune cell activation. Here, we investigate whether cow's milk consumption regulates gut-brain axis functions and affects patterns of behaviors in BALB/c mice, previously described by present low sociability, significant stereotypes, and restricted interest features. The major objectives consist of to investigate cow's milk supplementation as possible triggers interfering with cellular niches of the gut-brain axis and behavioral patterns. Male BALB/c at 6 weeks were randomly divided into two groups, one supplemented with cow's milk processed at ultra-high temperature (UHT) and another group receiving water (controls) three times per day (200 μL per dose) for one week. Milk consumption disturbed histological compartments of the small intestine, including niches of KI67+-proliferating cells and CD138+ Ig-secreting plasma cells. In the liver, milk intake was associated with pro-inflammatory responses, oxidative stress, and atypical glycogen distribution. Milk-supplemented mice showed significant increase in granulocytes (CD11b+SSChigh cells) and CD4+ T cells in the blood. These mice also had neuroinflammatory signals, including an enhanced number of cortical Iba-1+ microglial cells in the brain and significant cerebellar expression of nitric oxide synthase 2 by Purkinje cells. These phenotypes and tissue disorders in milk-supplemented mice were associated with atypical behaviors, including low sociability, high restricted interest, and severe stereotypies. Moreover, synaptic niches were also disturbed after milk consumption, and Shank-3+ and Drebrin+ post-synaptic cells were significantly reduced in the brain of these mice. Together, these data suggest that milk consumption interfered with the gut-brain axis in BALB/c mice and increased atypical behaviors, at least in part, linked to synapse dysfunctions, neuroinflammation, and oxidative stress regulation.

Combinatorial Wnt signaling landscape during brachiopod anteroposterior patterning

BackgroundWnt signaling pathways play crucial roles in animal development. They establish embryonic axes, specify cell fates, and regulate tissue morphogenesis from the early embryo to organogenesis. It is becoming increasingly recognized that these distinct developmental outcomes depend upon dynamic interactions between multiple ligands, receptors, antagonists, and other pathway modulators, consolidating the view that a combinatorial “code” controls the output of Wnt signaling. However, due to the lack of comprehensive analyses of Wnt components in several animal groups, it remains unclear if specific combinations always give rise to specific outcomes, and if these combinatorial patterns are conserved throughout evolution.ResultsIn this work, we investigate the combinatorial expression of Wnt signaling components during the axial patterning of the brachiopod Terebratalia transversa. We find that T. transversa has a conserved repertoire of ligands, receptors, and antagonists. These genes are expressed throughout embryogenesis but undergo significant upregulation during axial elongation. At this stage, Frizzled domains occupy broad regions across the body while Wnt domains are narrower and distributed in partially overlapping patches; antagonists are mostly restricted to the anterior end. Based on their combinatorial expression, we identify a series of unique transcriptional subregions along the anteroposterior axis that coincide with the different morphological subdivisions of the brachiopod larval body. When comparing these data across the animal phylogeny, we find that the expression of Frizzled genes is relatively conserved, whereas the expression of Wnt genes is more variable.ConclusionsOur results suggest that the differential activation of Wnt signaling pathways may play a role in regionalizing the anteroposterior axis of brachiopod larvae. More generally, our analyses suggest that changes in the receptor context of Wnt ligands may act as a mechanism for the evolution and diversification of the metazoan body axis.

A new motile animal with implications for the evolution of axial polarity from the Ediacaran of South Australia.

Fossils of the Ediacara Biota preserve the oldest evidence for complex, macroscopic animals. Most are difficult to constrain phylogenetically, however, the presence of rare, derived groups suggests that many more fossils from this period represent extant groups than are currently appreciated. One approach to recognize such early animals is to instead focus on characteristics widespread in animals today, for example multicellularity, motility, and axial polarity. Here, we describe a new taxon, Quaestio simpsonorum gen. et sp. nov. from the Ediacaran of South Australia. Quaestio is reconstructed with a thin external membrane connecting more resilient tissues with anterior-posterior polarity, left-right asymmetry and tentative evidence for dorsoventral differentiation. Associated trace fossils indicate an epibenthic and motile lifestyle. Our results suggest that Quaestio was a motile eumetazoan with a body plan not previously recognized in the Ediacaran, including definitive evidence of chirality. This organization, combined with previous evidence for axial patterning in a variety of other Ediacara taxa, demonstrates that metazoan body plans were well established in the Precambrian.

Canonical and Non-Canonical Wnt Signaling Generates Molecular and Cellular Asymmetries to Establish Embryonic Axes.

The formation of embryonic axes is a critical step during animal development, which contributes to establishing the basic body plan in each particular organism. Wnt signaling pathways play pivotal roles in this fundamental process. Canonical Wnt signaling that is dependent on β-catenin regulates the patterning of dorsoventral, anteroposterior, and left-right axes. Non-canonical Wnt signaling that is independent of β-catenin modulates cytoskeletal organization to coordinate cell polarity changes and asymmetric cell movements. It is now well documented that components of these Wnt pathways biochemically and functionally interact to mediate cell-cell communications and instruct cellular polarization in breaking the embryonic symmetry. The dysfunction of Wnt signaling disrupts embryonic axis specification and proper tissue morphogenesis, and mutations of Wnt pathway genes are associated with birth defects in humans. This review discusses the regulatory roles of Wnt pathway components in embryonic axis formation by focusing on vertebrate models. It highlights current progress in decoding conserved mechanisms underlying the establishment of asymmetry along the three primary body axes. By providing an in-depth analysis of canonical and non-canonical pathways in regulating cell fates and cellular behaviors, this work offers insights into the intricate processes that contribute to setting up the basic body plan in vertebrate embryos.

A human pluripotent stem cell-based somitogenesis model using microfluidics

Emerging human pluripotent stem cell (hPSC)-based embryo models are useful for studying human embryogenesis. Particularly, there are hPSC-based somitogenesis models using free-floating culture that recapitulate somite formation. Somitogenesis invivo involves intricately orchestrated biochemical and biomechanical events. However, none of the current somitogenesis models controls biochemical gradients or biomechanical signals in the culture, limiting their applicability to untangle complex biochemical-biomechanical interactions that drive somitogenesis. Herein, we develop a human somitogenesis model by confining hPSC-derived presomitic mesoderm (PSM) tissues in microfabricated trenches. Exogenous microfluidic morphogen gradients imposed on the PSM tissues cause axial patterning and trigger spontaneous rostral-to-caudal somite formation. A mechanical theory is developed to explain the size dependency between somites and the PSM. The microfluidic somitogenesis model is further exploited to reveal regulatory roles of cellular and tissue biomechanics in somite formation. This study presents a useful microengineered, hPSC-based model for understanding the biochemical and biomechanical events that guide somite formation.

Molecular analysis of a self-organizing signaling pathway for Xenopus axial patterning from egg to tailbud

Xenopus embryos provide a favorable material to dissect the sequential steps that lead to dorsal-ventral (D-V) and anterior-posterior (A-P) cell differentiation. Here, we analyze the signaling pathways involved in this process using loss-of-function and gain-of-function approaches. The initial step was provided by Hwa, a transmembrane protein that robustly activates early β-catenin signaling when microinjected into the ventral side of the embryo leading to complete twinned axes. The following step was the activation of Xenopus Nodal-related growth factors, which could rescue the depletion of β-catenin and were themselves blocked by the extracellular Nodal antagonists Cerberus-Short and Lefty. During gastrulation, the Spemann-Mangold organizer secretes a cocktail of growth factor antagonists, of which the BMP antagonists Chordin and Noggin could rescue simultaneously D-V and A-P tissues in β-catenin-depleted embryos. Surprisingly, this rescue occurred in the absence of any β-catenin transcriptional activity as measured by β-catenin activated Luciferase reporters. The Wnt antagonist Dickkopf (Dkk1) strongly synergized with the early Hwa signal by inhibiting late Wnt signals. Depletion of Sizzled (Szl), an antagonist of the Tolloid chordinase, was epistatic over the Hwa and Dkk1 synergy. BMP4 mRNA injection blocked Hwa-induced ectopic axes, and Dkk1 inhibited BMP signaling late, but not early, during gastrulation. Several unexpected findings were made, e.g., well-patterned complete embryonic axes are induced by Chordin or Nodal in β-catenin knockdown embryos, dorsalization by Lithium chloride (LiCl) is mediated by Nodals, Dkk1 exerts its anteriorizing and dorsalizing effects by regulating late BMP signaling, and the Dkk1 phenotype requires Szl.

Tissue-intrinsic beta-catenin signals antagonize Nodal-driven anterior visceral endoderm differentiation

The anterior-posterior axis of the mammalian embryo is laid down by the anterior visceral endoderm (AVE), an extraembryonic signaling center that is specified within the visceral endoderm. Current models posit that AVE differentiation is promoted globally by epiblast-derived Nodal signals, and spatially restricted by a BMP gradient established by the extraembryonic ectoderm. Here, we report spatially restricted AVE differentiation in bilayered embryo-like aggregates made from mouse embryonic stem cells that lack an extraembryonic ectoderm. Notably, clusters of AVE cells also form in pure visceral endoderm cultures upon activation of Nodal signaling, indicating that tissue-intrinsic factors can restrict AVE differentiation. We identify β-catenin activity as a tissue-intrinsic factor that antagonizes AVE-inducing Nodal signals. Together, our results show how an AVE-like population can arise through interactions between epiblast and visceral endoderm alone. This mechanism may be a flexible solution for axis patterning in a wide range of embryo geometries, and provide robustness to axis patterning when coupled with signal gradients.

Molecular mechanism of BMP signal control by Twisted gastrulation

Twisted gastrulation (TWSG1) is an evolutionarily conserved secreted glycoprotein which controls signaling by Bone Morphogenetic Proteins (BMPs). TWSG1 binds BMPs and their antagonist Chordin to control BMP signaling during embryonic development, kidney regeneration and cancer. We report crystal structures of TWSG1 alone and in complex with a BMP ligand, Growth Differentiation Factor 5. TWSG1 is composed of two distinct, disulfide-rich domains. The TWSG1 N-terminal domain occupies the BMP type 1 receptor binding site on BMPs, whereas the C-terminal domain binds to a Chordin family member. We show that TWSG1 inhibits BMP function in cellular signaling assays and mouse colon organoids. This inhibitory function is abolished in a TWSG1 mutant that cannot bind BMPs. The same mutation in the Drosophila TWSG1 ortholog Tsg fails to mediate BMP gradient formation required for dorsal-ventral axis patterning of the early embryo. Our studies reveal the evolutionarily conserved mechanism of BMP signaling inhibition by TWSG1.

Smad4 is essential for epiblast scaling and morphogenesis after implantation, but nonessential before implantation.

Bone morphogenic protein (BMP) signaling plays an essential and highly conserved role in embryo axial patterning in animal species. However, in mammalian embryos, which develop inside the mother, early development includes a preimplantation stage, which does not occur in externally developing embryos. During preimplantation, the epiblast is segregated from extra-embryonic lineages that enable implantation and development in utero. Yet, the requirement for BMP signaling is imprecisely defined in mouse early embryos. Here, we show that, in contrast to previous reports, BMP signaling (SMAD1/5/9 phosphorylation) is not detectable until implantation when it is detected in the primitive endoderm - an extra-embryonic lineage. Moreover, preimplantation development appears to be normal following deletion of maternal and zygotic Smad4, an essential effector of canonical BMP signaling. In fact, mice lacking maternal Smad4 are viable. Finally, we uncover a new requirement for zygotic Smad4 in epiblast scaling and cavitation immediately after implantation, via a mechanism involving FGFR/ERK attenuation. Altogether, our results demonstrate no role for BMP4/SMAD4 in the first lineage decisions during mouse development. Rather, multi-pathway signaling among embryonic and extra-embryonic cell types drives epiblast morphogenesis postimplantation.

An atlas of spider development at single-cell resolution provides new insights into arthropod embryogenesis

Spiders are a diverse order of chelicerates that diverged from other arthropods over 500 million years ago. Research on spider embryogenesis, particularly studies using the common house spider Parasteatoda tepidariorum, has made important contributions to understanding the evolution of animal development, including axis formation, segmentation, and patterning. However, we lack knowledge about the cells that build spider embryos, their gene expression profiles and fate. Single-cell transcriptomic analyses have been revolutionary in describing these complex landscapes of cellular genetics in a range of animals. Therefore, we carried out single-cell RNA sequencing of P. tepidariorum embryos at stages 7, 8 and 9, which encompass the establishment and patterning of the body plan, and initial differentiation of many tissues and organs. We identified 20 cell clusters, from 18.5 k cells, which were marked by many developmental toolkit genes, as well as a plethora of genes not previously investigated. We found differences in the cell cycle transcriptional signatures, suggestive of different proliferation dynamics, which related to distinctions between endodermal and some mesodermal clusters, compared with ectodermal clusters. We identified many Hox genes as markers of cell clusters, and Hox gene ohnologs were often present in different clusters. This provided additional evidence of sub- and/or neo-functionalisation of these important developmental genes after the whole genome duplication in an arachnopulmonate ancestor (spiders, scorpions, and related orders). We also examined the spatial expression of marker genes for each cluster to generate a comprehensive cell atlas of these embryonic stages. This revealed new insights into the cellular basis and genetic regulation of head patterning, hematopoiesis, limb development, gut development, and posterior segmentation. This atlas will serve as a platform for future analysis of spider cell specification and fate, and studying the evolution of these processes among animals at cellular resolution.

Asymmetric Segregation of Maternal mRNAs and Germline-related Determinants in Cephalochordate Embryos: Implications for the Evolution of Early Patterning Events in Chordates.

How animal embryos determine their early cell fates is an important question in developmental biology. In various model animals, asymmetrically localized maternal transcripts play important roles in axial patterning and cell fate specification. Cephalochordates (amphioxus), which have three living genera (Asymmetron, Epigonichthys, and Branchiostoma), are an early branching chordate lineage and thus occupy a key phylogenetic position for understanding the evolution of chordate developmental mechanisms. It has been shown that in the zygote of Branchiostoma amphioxus, which possesses bilateral gonads flanking both sides of their trunk region, maternal transcripts of germline determinants form a compact granule. During early embryogenesis, this granule is inherited by a single blastomere, which subsequently gives rise to a cluster of cells displaying typical characteristics of primordial germ cells (PGC). These PGCs then come to lie in the tailbud region and proliferate during posterior elongation of the larvae to join in the gonad anlagen at the ventral tip of the developing myomeres in amphioxus larvae. However, in Asymmetron and Epigonichthys amphioxus, whose gonads are present only on the right side of their bodies, nothing is known about their PGC development or the cellular/morphogenetic processes resulting in the asymmetric distribution of gonads. Using conserved germline determinants as markers, we show that similarly to Branchiostoma amphioxus, Asymmetron also employs a preformation mechanism to specify their PGCs, suggesting that this mechanism represents an ancient trait dating back to the common ancestor of Cephalochordates. Surprisingly, we found that Asymmetron PGCs are initially deposited on both sides of the body during early larval development; however, the left-side PGCs cease to exist in young juveniles, suggesting that PGCs are eliminated from the left body side during larval development or following metamorphosis. This is reminiscent of the PGC development in the sea urchin embryo, and we discuss the implications of this observation for the evolution of developmental mechanisms.

Analysis of SMAD1/5 target genes in a sea anemone reveals ZSWIM4-6 as a novel BMP signaling modulator.

BMP signaling has a conserved function in patterning the dorsal-ventral body axis in Bilateria and the directive axis in anthozoan cnidarians. So far, cnidarian studies have focused on the role of different BMP signaling network components in regulating pSMAD1/5 gradient formation. Much less is known about the target genes downstream of BMP signaling. To address this, we generated a genome-wide list of direct pSMAD1/5 target genes in the anthozoan Nematostella vectensis, several of which were conserved in Drosophila and Xenopus. Our ChIP-seq analysis revealed that many of the regulatory molecules with documented bilaterally symmetric expression in Nematostella are directly controlled by BMP signaling. We identified several so far uncharacterized BMP-dependent transcription factors and signaling molecules, whose bilaterally symmetric expression may be indicative of their involvement in secondary axis patterning. One of these molecules is zswim4-6, which encodes a novel nuclear protein that can modulate the pSMAD1/5 gradient and potentially promote BMP-dependent gene repression.

Comparative survey of coordinated regulation of hypothalamic–pituitary–somatotropic axis in golden pompano (Trachinotus ovatus) and humpback grouper (Cromileptes altivelis)

Hypothalamic–Pituitary–Somatotropic (HPS) axis is the essential endocrine system playing important roles in animal growth. Here, the HPS axis were characterized in golden pompano (Trachinotus ovatus) and humpback grouper (Cromileptes altivelis), two marine cultured tropical teleosts representing fast and slow growth patterns, respectively. Through genomic and transcriptomic survey, 32 and 35 HPS genes were characterized in T. ovatus and C. altivelis. Functional domain and phylogeny revealed their conserved function among teleost lineages, with more ssts and igfbps identified and actively expressed in C. altivelis than in T. ovatus. The regulation of HPS genes responding to external stimuli revealed that T. ovatus HPS genes, including gh, igf1/2, igfbp1a/b, igfbp2b and igfbp5b, were differentially expressed under temperature or starvation challenges, while C. altivelis HPS genes were sensitive to salinity change with sst1.2, ghrhrb, igf1, igf2r, igfbp1a and igfbp5a regulated in brains. Strong interactive connectivity of igfbps was found in both T. ovatus and C. altivelis. Moreover, HPS genes evolved differently between T. ovatus and C. altivelis, and positively selected sites were detected in more C. altivelis HPS genes, like in functional domains of igf1ra and igf1rb. The igf1ra evolved faster than igf1rb in teleosts, which may contribute to their functional divergence. In conclusion, this study represented different regulatory and evolutionary patterns of HPS axis between T. ovatus and C. altivelis, which are vital in regulating their growth and will provide comprehensive insights into the cultivation of T. ovatus and C. altivelis in aquaculture.

Evolutionarily conserved Wnt/Sp5 signaling is critical for anterior-posterior axis patterning in sea urchin embryos

Evolutionarily conserved Wnt/Sp5 signaling is critical for anterior-posterior axis patterning in sea urchin embryos

LIM-HD transcription factors control axial patterning and specify distinct neuronal and intestinal cell identities in planarians.

Adult planarians can regenerate the gut, eyes and even a functional brain. Proper identity and patterning of the newly formed structures require signals that guide and commit their adult stem cells. During embryogenesis, LIM-homeodomain (LIM-HD) transcription factors act in a combinatorial 'LIM code' to control cell fate determination and differentiation. However, our understanding about the role these genes play during regeneration and homeostasis is limited. Here, we report the full repertoire of LIM-HD genes in Schmidtea mediterranea. We found that lim homeobox (lhx) genes appear expressed in complementary patterns along the cephalic ganglia and digestive system of the planarian, with some of them being co-expressed in the same cell types. We have identified that Smed-islet1, -lhx1/5-1, -lhx2/9-3, -lhx6/8, -lmx1a/b-2 and -lmx1a/b-3 are essential to pattern and size the planarian brain as well as for correct regeneration of specific subpopulations of dopaminergic, serotonergic, GABAergic and cholinergic neurons, while Smed-lhx1/5.2 and -lhx2/9.2 are required for the proper expression of intestinal cell type markers, specifically the goblet subtype. LIM-HD are also involved in controlling axonal pathfinding (lhx6/8), axial patterning (islet1, lhx1/5-1, lmx1a/b-3), head/body proportions (islet2) and stem cell proliferation (lhx3/4, lhx2/9-3, lmx1a/b-2, lmx1a/b-3). Altogether, our results suggest that planarians might present a combinatorial LIM code that controls axial patterning and axonal growing and specifies distinct neuronal and intestinal cell identities.

Single Cell Multimodal Analyses Reveal Epigenomic and Transcriptomic Basis for Birth Defects in Maternal Diabetes.

Maternal diabetes mellitus is among the most frequent environmental contributors to congenital birth defects, including heart defects and craniofacial anomalies, yet the cell types affected and mechanisms of disruption are largely unknown. Using multi-modal single cell analyses, here we show that maternal diabetes affects the epigenomic landscape of specific subsets of cardiac and craniofacial progenitors during embryogenesis. A previously unrecognized cardiac progenitor subpopulation expressing the homeodomain-containing protein ALX3 showed prominent chromatin accessibility changes and acquired a more posterior identity. Similarly, a subpopulation of neural crest-derived cells in the second pharyngeal arch, which contributes to craniofacial structures, displayed abnormalities in the epigenetic landscape and axial patterning defects. Chromatin accessibility changes in both populations were associated with increased retinoic acid signaling, known to establish anterior-posterior identity. This work highlights how an environmental insult can have highly selective epigenomic consequences on discrete cell types leading to developmental patterning defects.

Thumb Metacarpophalangeal Joint Kinematics and Elongation of the Ulnar Collateral Ligament

The purpose of the study was to determine if the sphericity of the thumb metacarpophalangeal (MCP) joint influences the joint's rotational axis (RA) and elongation patterns of the ulnar collateral ligament (UCL). Ulnar collateral ligament origins and attachments of 28 fresh-frozen cadaveric thumbs were marked with a radiopaque marker. Lateral radiographs were obtained in neutral and 20°, 40°, and 60° of flexion. The dorsal and palmar joint gap and the length of four different UCL portions were digitally measured in all flexion states. The RA was determined by the intersection of the midshaft axis of the proximal phalanx in neutral and flexion states. Sphericity of the MCP joint was assessed using morphometric parameters. Joints were grouped as round or flat. Differences in all measured parameters between groups were analyzed. During flexion, the dorsal joint gap increased by 322% in flat joints and 163% in round joints. The palmar joint gap decreased to 45% in flat joints and to 87% in round joints. The RA was at 29% of metacarpal height and 96% of metacarpal length in flat joints and at 40% of height and 86% of length in round joints. Maximum UCL elongation (111%) was noted at 40° flexion in the dorsal proper UCL in flat joints and at 60° flexion in the accessory UCL (117%) in round joints. In flat MCP joints, the RA is more dorsal and distal in the metacarpal head compared to round joints, resulting in a hinged flexion motion. Elongation of the UCL is highest at end flexion in round joints and highest at midflexion in flat joints. The different kinematics of flat and round MCP joints may contribute to the understanding of the pathophysiology of UCL ruptures. The propensity of this injury and the position in which they occur may be affected by the MCP joint morphology.