Axial Patterning Research Articles

Periodic inhibition of Erk activity drives sequential somite segmentation.

Sequential segmentation creates modular body plans of diverse metazoan embryos1-4. Somitogenesis establishes the segmental pattern of the vertebrate body axis. A molecular segmentation clock in the presomitic mesoderm sets the pace of somite formation4. However, how cells are primed to form a segment boundary at a specific location remains unclear. Here we developed precise reporters for the clock and double-phosphorylated Erk (ppErk) gradient in zebrafish. We show that the Her1-Her7 oscillator drives segmental commitment by periodically lowering ppErk, therefore projecting its oscillation onto the ppErk gradient. Pulsatile inhibition of the ppErk gradient can fully substitute for the role of the clock, and kinematic clock waves are dispensable for sequential segmentation. The clock functions upstream of ppErk, which in turn enables neighbouring cells to discretely establish somite boundaries in zebrafish5. Molecularly divergent clocks and morphogen gradients were identified in sequentially segmenting species3,4,6-8. Our findings imply that versatile clocks may establish sequential segmentation in diverse species provided that they inhibit gradients.

Topological steering of light by nematic vortices and analogy to cosmic strings.

Liquid crystals are widely known for their technological uses in displays, electro-optics, photonics and nonlinear optics, but these applications typically rely on defining and switching non-topological spatial patterns of the optical axis. Here, we demonstrate how a liquid crystal's optical axis patterns with singular vortex lines can robustly steer beams of light. External stimuli, including an electric field and light itself, allow us to reconfigure these unusual light-matter interactions. Periodic arrays of vortices obtained by photo-patterning enable the vortex-mediated fission of optical solitons, yielding their lightning-like propagation patterns. Predesigned patterns and spatial trajectories of vortex lines in high-birefringence liquid crystals can steer light into closed loops or even knots. Our vortex lattices might find technological uses in beam steering, telecommunications, virtual reality implementations and anticounterfeiting, as well as possibly offering a model system for probing the interaction of light with defects, including the theoretically predicted, imagination-capturing light-steering action of cosmic strings, elusive defects in cosmology.

Instantaneous mapping of liquid crystal orientation using a polychromatic polarizing microscope

ABSTRACT Polarising microscopy brought about many advancements in the science of liquid crystals and other soft materials, including those of biological origin. Recent developments in optics and computer-based analysis have enabled a new generation of quantitative polarising microscopy which produces spatial maps of the optic axis. Unfortunately, most of the available approaches require a long acquisition time of multiple images which are then analysed to produce the map. We describe a polychromatic polarising microscope, which allows one to map the patterns of the optical axis in a single-shot exposure, thus enabling a fast temporal resolution. We present a comparative analysis of the new microscope with alternative techniques such as a conventional polarising optical microscope and MicroImager of Hinds Instruments.

An ancestral Wnt-Brachyury feedback loop in axial patterning and recruitment of mesoderm-determining target genes.

Transcription factors are crucial drivers of cellular differentiation during animal development and often share ancient evolutionary origins. The T-box transcription factor Brachyury plays a pivotal role as an early mesoderm determinant and neural repressor in vertebrates; yet, the ancestral function and key evolutionary transitions of the role of this transcription factor remain obscure. Here, we present a genome-wide target-gene screen using chromatin immunoprecipitation sequencing in the sea anemone Nematostella vectensis, an early branching non-bilaterian, and the sea urchin Strongylocentrotus purpuratus, a representative of the sister lineage of chordates. Our analysis reveals an ancestral gene regulatory feedback loop connecting Brachyury, FoxA and canonical Wnt signalling involved in axial patterning that predates the cnidarian-bilaterian split about 700 million years ago. Surprisingly, we also found that part of the gene regulatory network controlling the fate of neuromesodermal progenitors in vertebrates was already present in the common ancestor of cnidarians and bilaterians. However, while several endodermal and neuronal Brachyury target genes are ancestrally shared, hardly any of the key mesodermal downstream targets in vertebrates are found in the sea anemone or the sea urchin. Our study suggests that a limited number of target genes involved in mesoderm formation were newly acquired in the vertebrate lineage, leading to a dramatic shift in the function of this ancestral developmental regulator.

Transmembrane anterior posterior transformation 1 regulates BMP signaling and modulates the protein stability of SMAD1/5

The bone morphogenetic protein (BMP) signaling pathway plays pivotal roles in various biological processes during embryogenesis and adult homeostasis. Transmembrane anterior posterior transformation 1 (TAPT1) is an evolutionarily conserved protein involved in murine axial skeletal patterning. Genetic defects in TAPT1 result in complex lethal osteochondrodysplasia. However, the specific cellular activity of TAPT1 is not clear. Herein, we report that TAPT1 inhibits BMP signaling and destabilizes the SMAD1/5 protein by facilitating its interaction with SMURF1 E3 ubiquitin ligase, which leads to SMAD1/5 proteasomal degradation. In addition, we found that the activation of BMP signaling facilitates the redistribution of TAPT1 and promotes its association with SMAD1. TAPT1-deficient murine C2C12 myoblasts or C3H/10T1/2 mesenchymal stem cells exhibit elevated SMAD1/5/9 protein levels, which amplifies BMP activation, in turn leading to a boost in the transdifferentiation or differentiation processing of these distinct TAPT1-deficient cell lines changing into mature osteoblasts. Furthermore, the enhancing effect of TAPT1 deficiency on osteogenic differentiation of C3H/10T1/2cells was observed in an invivo ectopic bone formation model. Importantly, a subset of TAPT1 mutations identified in humans with lethal skeletal dysplasia exhibited gain-of-function activity on SMAD1 protein levels. Thus, this finding elucidates the role of TAPT1 in the regulation of SMAD1/5 protein stability for controlling BMP signaling.

Developmental toxicity of remdesivir, an anti-COVID-19 drug, is implicated by in vitro assays using morphogenetic embryoid bodies of mouse and human pluripotent stem cells.

Remdesivir is an antiviral drug approved for the treatment of COVID-19, whose developmental toxicity remains unclear. More information about the safety of remdesivir is urgently needed for people of childbearing potential, who are affected by the ongoing pandemic. Morphogenetic embryoid bodies (MEBs) are three-dimensional (3D) aggregates of pluripotent stem cells that recapitulate embryonic body patterning in vitro, and have been used as effective embryo models to detect the developmental toxicity of chemical exposures specifically and sensitively. MEBs were generated from mouse P19C5 and human H9 pluripotent stem cells, and used to examine the effects of remdesivir. The morphological effects were assessed by analyzing the morphometric parameters of MEBs after exposure to varying concentrations of remdesivir. The molecular impact of remdesivir was evaluated by measuring the transcript levels of developmental regulator genes. The mouse MEB morphogenesis was impaired by remdesivir at 1-8μM. Remdesivir affected MEBs in a manner dependent on metabolic conversion, and its potency was higher than GS-441524 and GS-621763, presumptive anti-COVID-19 drugs that act similarly to remdesivir. The expressions of developmental regulator genes, particularly those involved in axial and somite patterning, were dysregulated by remdesivir. The early stage of MEB development was more vulnerable to remdesivir exposure than the later stage. The morphogenesis and gene expression profiles of human MEBs were also impaired by remdesivir at 1-8μM. Remdesivir impaired mouse and human MEBs at concentrations that are comparable to the therapeutic plasma levels in humans, urging further investigation into the potential impact of remdesivir on developing embryos.

Homologous gene regulatory networks control development of apical organs and brains in Bilateria.

Apical organs are relatively simple larval nervous systems. The extent to which apical organs are evolutionarily related to the more complex nervous systems of other animals remains unclear. To identify common developmental mechanisms, we analyzed the gene regulatory network (GRN) controlling the development of the apical organ in sea urchins. We characterized the developmental expression of 30 transcription factors and identified key regulatory functions for FoxQ2, Hbn, Delta/Notch signaling, and SoxC in the patterning of the apical organ and the specification of neurons. Almost the entire set of apical transcription factors is expressed in the nervous system of worms, flies, zebrafish, frogs, and mice. Furthermore, a regulatory module controlling the axial patterning of the vertebrate brain is expressed in the ectoderm of sea urchin embryos. We conclude that GRNs controlling the formation of bilaterian nervous systems share a common origin and that the apical GRN likely resembles an ancestral regulatory program.

Crystallographic preferred orientation (CPO) patterns in uniaxially compressed deuterated ice: quantitative analysis of historical data

AbstractStrain, temperature and strain rate are crucial factors governing the development of crystallographic preferred orientations (CPO) in ice. To better understand how CPO patterns change in response to these variables, we performed quantitative analyses on neutron diffraction data between 2010 and 2019, collected in situ during uniaxial compression experiments on deuterium ice. At strains >10% and temperatures <−10°C, thec-axis pattern switches from a single maximum (‘cluster’) to small circle (‘cone’), both oriented parallel to shortening. The diameter and mean width of the cone pattern decrease as strain and/or strain rate increases. Prismatic axis (aandm) patterns are characterised by great circles parallel to the pole figure margin and may be distinguishable from the patterns in ice deformed under simple shear. While strain has the main influence on the degree of preferred orientation (or CPO ‘strength’), both temperature and strain rate have minor influences, which limits the extent to which CPOs can be used to measure strain. As cluster patterns can be observed in thec-axes of ice deformed under both pure and simple shear settings, this may complicate interpretations of flow geometry in terrestrial ice unless the prismatic axis patterns are also considered.

Sea anemone Frizzled receptors play partially redundant roles in oral-aboral axis patterning.

Canonical Wnt (cWnt) signalling is involved in a plethora of basic developmental processes such as endomesoderm specification, gastrulation and patterning the main body axis. To activate the signal, Wnt ligands form complexes with LRP5/6 and Frizzled receptors, which leads to nuclear translocation of β-catenin and a transcriptional response. In Bilateria, the expression of different Frizzled genes is often partially overlapping, and their functions are known to be redundant in several developmental contexts. Here, we demonstrate that all four Frizzled receptors take part in the cWnt-mediated oral-aboral axis patterning in the cnidarian Nematostella vectensis but show partially redundant functions. However, we do not see evidence for their involvement in the specification of the endoderm - an earlier event likely relying on maternal intracellular β-catenin signalling components. Finally, we demonstrate that the main Wnt ligands crucial for the early oral-aboral patterning are Wnt1, Wnt3 and Wnt4. Comparison of our data with knowledge from other models suggests that distinct but overlapping expression domains and partial functional redundancy of cnidarian and bilaterian Frizzled genes may represent a shared ancestral trait.

SiRNA-mediated gene knockdown via electroporation in hydrozoan jellyfish embryos

As the sister group to bilaterians, cnidarians stand in a unique phylogenetic position that provides insight into evolutionary aspects of animal development, physiology, and behavior. While cnidarians are classified into two types, sessile polyps and free-swimming medusae, most studies at the cellular and molecular levels have been conducted on representative polyp-type cnidarians and have focused on establishing techniques of genetic manipulation. Recently, gene knockdown by delivery of short hairpin RNAs into eggs via electroporation has been introduced in two polyp-type cnidarians, Nematostella vectensis and Hydractinia symbiolongicarpus, enabling systematic loss-of-function experiments. By contrast, current methods of genetic manipulation for most medusa-type cnidarians, or jellyfish, are quite limited, except for Clytia hemisphaerica, and reliable techniques are required to interrogate function of specific genes in different jellyfish species. Here, we present a method to knock down target genes by delivering small interfering RNA (siRNA) into fertilized eggs via electroporation, using the hydrozoan jellyfish, Clytia hemisphaerica and Cladonema paciificum. We show that siRNAs targeting endogenous GFP1 and Wnt3 in Clytia efficiently knock down gene expression and result in known planula phenotypes: loss of green fluorescence and defects in axial patterning, respectively. We also successfully knock down endogenous Wnt3 in Cladonema by siRNA electroporation, which circumvents the technical difficulty of microinjecting small eggs. Wnt3 knockdown in Cladonema causes gene expression changes in axial markers, suggesting a conserved Wnt/β-catenin-mediated pathway that controls axial polarity during embryogenesis. Our gene-targeting siRNA electroporation method is applicable to other animals, including and beyond jellyfish species, and will facilitate the investigation and understanding of myriad aspects of animal development.

HOX-Gene Cluster Organization and Genome Duplications in Fishes and Mammals: Transcript Variant Distribution along the Anterior-Posterior Axis.

Hox genes play a crucial role in morphogenesis, especially in anterior–posterior body axis patterning. The organization of Hox clusters in vertebrates is a result of several genome duplications: two rounds of duplication in the ancestors of all vertebrates and a third round that was specific for teleost fishes. Teleostei cluster structure has been significantly modified in the evolutionary processes by Hox gene losses and co-options, while mammals show no such tendency. In mammals, the Hox gene number in a single cluster is stable and generally large, and the numbers are similar to those in the Chondrichthyes. Hox gene alternative splicing activity slightly differs between fishes and mammals. Fishes and mammals have differences in their known alternative splicing activity for Hox gene distribution along the anterior–posterior body axis. The analyzed fish groups—the Coelacanthiformes, Chondrichthyes, and Teleostei—all have higher known alternative mRNA numbers from the anterior and posterior regions, whereas mammals have a more uniform Hox transcript distribution along this axis. In fishes, most Hox transcripts produce functioning proteins, whereas mammals have significantly more known transcripts that do not produce functioning proteins.

Yoga as an Escape from Depreciating Mental Health due to COVID 19: A Qualitative study analyzing the factors associated with mental status based on the experiences of geriatric population's participation in an Online program during COVID 19 lockdown in India.

The COVID-19 pandemic has left an array of direct physical consequences unevenly on the elderly apart from leaving a wide range of indirect consequences of mental health problems on them. This study aims to understand the effect of a Yoga-Meditation based mobile phone application intervention to reduce the duress by mental health issues via a qualitative analysis. A phenomenological qualitative succession of an explanatory sequential design of a prior quantitative study followed by a Yoga-Meditation mobile phone based intervention, where 30 participants who had mild or moderate Depression, Anxiety or Stress as assessed by DASS-21 were chosen by random sampling and were asked to take part in an interview. The interview was transcribed, coded, patterns identified and themes were created to understand the perceptions. Three major schools of thought were identified and explored to understand the general perception of Mental health, COVID-19 and the intervention: a) Knowledge Axis patterns of COVID-19, which included their prior knowledge about the disease, its consequences and their cues to action based on those beliefs, b) Mental Health and Strategies to Positivity, involves all their actions to promote, restore or propagate a positive mental attitude from religious activities to physical activities and c) Application related thoughts, involved their perceptions of the app, the barriers to use and suggestions to improve. This study gave deeper insight into the schools of thought which will be important in designing future interventions and yoga-meditation based programs in the future, essentially for geriatric populations as it serves as a feasible simple measure for the same.

Intrinsically disordered BMP4 morphogen and the beak of the finch: Co-option of an ancient axial patterning system

Darwin's finches, with the primary diversity in the shape and size of their beaks, represent an excellent model system to study speciation and adaptive evolution. It is generally held that evolution depends on the natural selection of heritable phenotypic variations originating from the genetic mutations. However, it is now increasingly evident that epigenetic transgenerational inheritance of phenotypic variation can also guide evolutionary change. Several studies have shown that the bone morphogenetic protein BMP4 is a major driver of beak morphology. A recent study explored variability of the morphological, genetic, and epigenetic differences in the adjacent “urban” and “rural” populations of two species of Darwin's finches on the Galápagos Islands and revealed significant changes in methylation patterns in several genes including those involved in the BMP/TGFß pathway in the sperm DNA compared to erythrocyte DNA. These observations indicated that epigenetic changes caused by environmental fluctuations can be passed on to the offspring. Nonetheless, the mechanism by which dysregulated expression of BMP4 impacts beak morphology remains poorly understood. Here, we show that BMP4 is an intrinsically disordered protein and present a causal a link between epigenetic changes, BMP4 dysregulation and the evolution of the beak of the finch by natural selection.

Topographic Pattern of Keratoconus patient at First Presentation in Tertiary Eye Hospital of Bangladesh

Objective: To evaluate the topographic pattern of keratoconus patient at first presentation in a tertiary eye hospital of Bangladesh.
 Methods: This was a cross sectional study conducted over 200 eyes of 100 keratoconus patients attending at National Institute of Ophthalmology & Hospital, Dhaka, for a period of 6 months. Selected patients underwent detail history, ocular and systemic examination as well as related investigations which includes corneal topography, keratometry and auto refractometry.
 Results: Mean age of the patients was 21.24 ± 6.25(SD) years and among the patients male predominance was observed, male to female ratio was 2.1:1. The mean unaided visual acuity of better eye was 0.86 ± 0.38(SD) Log MAR and mean unaided visual acuity of worse eye was 1.16 ± 0.44 Log MAR. Among 200 eyes there were 36 mild (18.0%), 100 moderate (50.0%) and 64 severe (32.0%) keratoconus eyes. Majority of the eyes (81.0%) showed three common topographic pattern, these are asymmetric bowtie with skewed axis (32.0%), asymmetric bowtie with inferior steepening (30.0%) and inferior steepening (19.0%). In mild keratoconus patients topography showed largely one pattern, inferior steepening (30.6% of mild keratoconus). In case of moderate keratoconus patients topography shows mainly three patterns, asymmetrical bowtie with skewed axis (19.0%), asymmetric bowtie with inferior steepening (16.5%) and inferior steepening (10.5%). In severe keratoconus patients topography shows mainly three patterns, asymmetrical bowtie with inferior steepening (10.5%), asymmetric bowtie with skewed axis (9.5%) and irregular pattern (8.5%). There was no round, superior steepening, symmetric bowtie or asymmetric bowtie with superior steepening pattern in severe keratoconus.
 Conclusion: The pattern of topography varies among the different stages of keratoconus patients. From the topography pattern we can diagnose the keratoconus early and also get the information of severity of the disease and treat accordingly.
 J. Natl. Inst. Ophthalmol. 2022; 5(2):31-36

Spatial profiling of early primate gastrulation in utero.

Gastrulation controls the emergence of cellular diversity and axis patterning in the early embryo. In mammals, this transformation is orchestrated by dynamic signalling centres at the interface of embryonic and extraembryonic tissues1-3. Elucidating the molecular framework of axis formation in vivo is fundamental for our understanding of human development4-6 and to advance stem-cell-based regenerative approaches7. Here we illuminate early gastrulation of marmoset embryos in utero using spatial transcriptomics and stem-cell-based embryo models. Gaussian process regression-based 3D transcriptomes delineate the emergence of the anterior visceral endoderm, which is hallmarked by conserved (HHEX, LEFTY2, LHX1) and primate-specific (POSTN, SDC4, FZD5) factors. WNT signalling spatially coordinates the formation of the primitive streak in the embryonic disc and is counteracted by SFRP1 and SFRP2 to sustain pluripotency in the anterior domain. Amnion specification occurs at the boundaries of the embryonic disc through ID1, ID2 and ID3 in response to BMP signalling, providing a developmental rationale for amnion differentiation of primate pluripotent stem cells(PSCs). Spatial identity mapping demonstrates that primed marmoset PSCs exhibit the highest similarity to the anterior embryonic disc, whereas naive PSCs resemble the preimplantation epiblast. Our 3D transcriptome models reveal the molecular code of lineage specification in the primate embryo and provide an in vivo reference to decipher human development.

Electrical and thermal stability of Al-Cu welds: Performance benchmarking of the hybrid metal extrusion and bonding process

Advances in joining processes for aluminum and copper are sought after to facilitate the greater adoption of aluminum in electrical applications. Aluminum's chemical affinity to copper causes the joining and lifetime of Al-Cu welds to be vulnerable to the formation of various intermetallic compounds. Intermetallic compounds and the resulting weld structure are known to reduce the structural integrity and increase the electrical resistance of Al-Cu welds. In this study we evaluate the novel joining process, Hybrid Metal Extrusion and Bonding, for butt welding aluminum and copper. The weld structure was examined using scanning and transmission electron microscopy, and the weld resistance was measured using four-point measurements forecast to the weld interface. Energy dispersive spectroscopy and electron diffraction zone axis patterns were analysed to identify intermetallic compounds. Weld samples were examined pre and post heat treatment at 200 °C, 250 °C and 350 °C for total durations of over 1000 h. The results are compared to existing Al-Cu joining processes, and a new metric, weld interface resistivity, is proposed to compare the electrical properties of bimetallic welds. The Hybrid Metal Extrusion and Bonding process was found to form a thin, consistent and straight intermetallic layer with negligible impact on electrical resistance in the as-welded condition. Artificial ageing of samples by heat treatment established the overall growth rate of intermetallic compounds. The growth rate was used to evaluate the weld's operational lifetime versus temperature. The intermetallic growth rate of Hybrid Metal Extrusion and Bonding was quantified at 200 °C and compared to alternative processes. The Hybrid Metal Extrusion and Bonding process showed a significant performance advantage requiring the longest time to reach 2 μm thickness. Furthermore, the growth of intermetallic compounds did not increase the electrical resistance of the weld interface. The negligible impact on electrical resistance and slow intermetallic growth are promising results of the potential functional performance. This study is the first characterisation of the Hybrid Metal Extrusion and Bonding process for electrical applications showcasing its exciting potential for the joining of aluminum and copper.

Mineralocorticoid receptor and glucocorticoid receptor work alone and together in cell-type-specific manner: Implications for resilience prediction and targeted therapy

‘You can't roll the clock back and reverse the effects of experiences' Bruce McEwen used to say when explaining how allostasis labels the adaptive process. Here we will for once roll the clock back to the times that the science of the glucocorticoid hormone was honored with a Nobel prize and highlight the discovery of their receptors in the hippocampus as inroad to its current status as master regulator in control of stress coping and adaptation. Glucocorticoids operate in concert with numerous neurotransmitters, neuropeptides, and other hormones with the aim to facilitate processing of information in the neurocircuitry of stress, from anticipation and perception of a novel experience to behavioral adaptation and memory storage. This action, exerted by the glucocorticoids, is guided by two complementary receptor systems, mineralocorticoid receptors (MR) and glucocorticoid receptors (GR), that need to be balanced for a healthy stress response pattern. Here we discuss the cellular, neuroendocrine, and behavioral studies underlying the MR:GR balance concept, highlight the relevance of hypothalamic-pituitary-adrenal (HPA) -axis patterns and note the limited understanding yet of sexual dimorphism in glucocorticoid actions. We conclude with the prospect that (i) genetically and epigenetically regulated receptor variants dictate cell-type-specific transcriptome signatures of stress-related neuropsychiatric symptoms and (ii) selective receptor modulators are becoming available for more targeted treatment. These two new developments may help to ‘restart the clock’ with the prospect to support resilience.

A New Probe Into the Innermost Inner Core Anisotropy via the Global Coda‐Correlation Wavefield

AbstractInvestigations of the Earth's inner core (IC) using seismic body waves are limited by their volumetric sampling due to uneven global distribution of large earthquakes and receivers. The sparse coverage of the IC leads to uncertainties in its anisotropy, the directional dependence of seismic velocity. Yet, detailed constraints on anisotropy, such as its magnitude, and spatial distribution, are required to understand the crystallographic structure of IC's iron and its solidification and deformation processes. Here, we present a new method to investigate the IC's anisotropic properties based on Earth's coda‐correlation wavefield constructed from the late coda of large earthquakes. We perform a comprehensive travel time analysis of I2*, an IC‐sensitive correlation feature identified as a counterpart of the direct seismic wavefield's PKIKPPKIKP waves, yet fundamentally different. Namely, I2* is a mathematical manifestation of similarity among specific seismic phases with the same slowness detected in global correlograms in the short inter‐receiver distance range. Our new spatial sampling of the IC overcomes the shortage of direct seismic wavefield paths sensitive to the IC's central volume, also known as the innermost IC (IMIC). The observed I2*’s travel time variations relative to Earth's rotation axis (ERA) support a model of cylindrical anisotropy with 3.3% strength and a zonal pattern of slow axis oriented 55° from ERA. We thus find compelling evidence for a deep IC structure with distinct anisotropy, although we cannot resolve the depth at which the change occurs. This finding reinforces previous inference on the IMIC, with implications for Earth's evolution.

Transcriptional Regulation and Implications for Controlling Hox Gene Expression.

Hox genes play key roles in axial patterning and regulating the regional identity of cells and tissues in a wide variety of animals from invertebrates to vertebrates. Nested domains of Hox expression generate a combinatorial code that provides a molecular framework for specifying the properties of tissues along the A–P axis. Hence, it is important to understand the regulatory mechanisms that coordinately control the precise patterns of the transcription of clustered Hox genes required for their roles in development. New insights are emerging about the dynamics and molecular mechanisms governing transcriptional regulation, and there is interest in understanding how these may play a role in contributing to the regulation of the expression of the clustered Hox genes. In this review, we summarize some of the recent findings, ideas and emerging mechanisms underlying the regulation of transcription in general and consider how they may be relevant to understanding the transcriptional regulation of Hox genes.

Minimal Developmental Computation: A Causal Network Approach to Understand Morphogenetic Pattern Formation.

What information-processing strategies and general principles are sufficient to enable self-organized morphogenesis in embryogenesis and regeneration? We designed and analyzed a minimal model of self-scaling axial patterning consisting of a cellular network that develops activity patterns within implicitly set bounds. The properties of the cells are determined by internal ‘genetic’ networks with an architecture shared across all cells. We used machine-learning to identify models that enable this virtual mini-embryo to pattern a typical axial gradient while simultaneously sensing the set boundaries within which to develop it from homogeneous conditions—a setting that captures the essence of early embryogenesis. Interestingly, the model revealed several features (such as planar polarity and regenerative re-scaling capacity) for which it was not directly selected, showing how these common biological design principles can emerge as a consequence of simple patterning modes. A novel “causal network” analysis of the best model furthermore revealed that the originally symmetric model dynamically integrates into intercellular causal networks characterized by broken-symmetry, long-range influence and modularity, offering an interpretable macroscale-circuit-based explanation for phenotypic patterning. This work shows how computation could occur in biological development and how machine learning approaches can generate hypotheses and deepen our understanding of how featureless tissues might develop sophisticated patterns—an essential step towards predictive control of morphogenesis in regenerative medicine or synthetic bioengineering contexts. The tools developed here also have the potential to benefit machine learning via new forms of backpropagation and by leveraging the novel distributed self-representation mechanisms to improve robustness and generalization.