ABSTRACT Brain tumours are the commonest solid neoplasms in children, accounting for one quarter of all childhood cancers. Our growing knowledge of basic developmental mechanisms has significantly contributed to understanding the pathogenesis of these tumours and is beginning to impact clinical decisions on how children with these diseases are treated.

ABSTRACT The sizes of living organisms span over 20 orders of magnitude or so. This daunting observation could intimidate researchers aiming to understand the general mechanisms controlling growth. However, recent progress suggests the existence of principles common to organisms as diverse as fruit flies, mice and humans. As we review here, these studies have provided insights into both autonomous and non-autonomous mechanisms controlling organ growth as well as some of the principles underlying growth coordination between organs and across bilaterally symmetrical organisms. This research tackles several aspects of developmental biology and integrates inputs from physics, mathematical modelling and evolutionary biology. Although many open questions remain, this work also helps to shed light on medically related conditions such as tissue and limb regeneration, as well as metabolic homeostasis and cancer.

ABSTRACT Developmental biology has grown into a data intensive science with the development of high-throughput imaging and multi-omics approaches. Machine learning is a versatile set of techniques that can help make sense of these large datasets with minimal human intervention, through tasks such as image segmentation, super-resolution microscopy and cell clustering. In this Spotlight, I introduce the key concepts, advantages and limitations of machine learning, and discuss how these methods are being applied to problems in developmental biology. Specifically, I focus on how machine learning is improving microscopy and single-cell ‘omics’ techniques and data analysis. Finally, I provide an outlook for the futures of these fields and suggest ways to foster new interdisciplinary developments.

ABSTRACT Planar cell polarity (PCP) reflects cellular orientation within the plane of an epithelium. PCP is crucial during many biological patterning processes and for organ function. It is omnipresent, from convergent-extension mechanisms during early development through to terminal organogenesis, and it regulates many aspects of cell positioning and orientation during tissue morphogenesis, organ development and homeostasis. Suzanne Eaton used the power of Drosophila as a model system to study PCP, but her vision of, and impact on, PCP studies in flies translates to all animal models. As I highlight here, Suzanne's incorporation of quantitative biophysical studies of whole tissues, integrated with the detailed cell biology of PCP phenomena, completely changed how the field studies this intriguing feature. Moreover, Suzanne's impact on ongoing and future PCP studies is fundamental, long-lasting and transformative.

ABSTRACT Members of the Hedgehog family of morphogens mediate the intercellular communication necessary for the organisation and development of many animal tissues. They are modified by various lipid adducts, rendering them insoluble in hydrophilic environments and leading to the contentious question of how these molecules travel in the aqueous extracellular space. Seminal work carried out by Suzanne Eaton and her colleagues has shed light on how these morphogens can spread over long distances through their association with lipoprotein particles. In this Spotlight article, we discuss Suzanne's pioneering work and her contribution to our understanding of the transport and activity of morphogens, in particular Hedgehog. We also describe two other essential aspects of her work: the discovery and characterisation of endogenously present Hedgehog variants, as well as her proposition that, in addition to its role as a morphogen, Hedgehog acts as an endocrine hormone.

ABSTRACT One of the central questions in developmental biology concerns how cells become organized into tissues of the correct size, shape and polarity. This organization depends on the implementation of a cell's genetic information to give rise to specific and coordinated cell behaviors, including cell division and cell shape change. The execution of these cell behaviors requires the active generation of mechanical forces. However, understanding how force generation is controlled and, importantly, coordinated among many cells in a tissue was little explored until the early 2000s. Suzanne Eaton was one of the pioneers in this emerging field of developmental tissue mechanics. As we briefly review here, she connected the quantitative analysis of cell behaviors with genetic assays, and integrated physical modeling with measurements of mechanical forces to reveal fundamental insights into epithelial morphogenesis at cell- and tissue-level scales.

ABSTRACT Lipids exert diverse functions in living organisms. They form cellular membranes, store and transport energy and play signalling roles. Some lipid species function in all of these processes, making them ideal candidates to coordinate metabolism with cellular homeostasis and animal development. This theme was central to Suzanne Eaton's research in the fruit fly, Drosophila . Here, we discuss her work on membrane lipid homeostasis in changing environments and on functions for lipids in the Hedgehog signalling pathway. We further highlight lipoproteins as inter-organ carriers of lipids and lipid-linked morphogens, which communicate dietary and developmental signals throughout the organism.

ABSTRACT Almost all animals undergo embryonic development, going from a single-celled zygote to a complex multicellular adult. We know that the patterning and morphogenetic processes involved in development are deeply conserved within the animal kingdom. However, the origins of these developmental processes are just beginning to be unveiled. Here, we focus on how the protist lineages sister to animals are reshaping our view of animal development. Most intriguingly, many of these protistan lineages display transient multicellular structures, which are governed by similar morphogenetic and gene regulatory processes as animal development. We discuss here two potential alternative scenarios to explain the origin of animal embryonic development: either it originated concomitantly at the onset of animals or it evolved from morphogenetic processes already present in their unicellular ancestors. We propose that an integrative study of several unicellular taxa closely related to animals will allow a more refined picture of how the last common ancestor of animals underwent embryonic development.

ABSTRACT Next-generation sequencing has greatly accelerated the discovery of rare human genetic diseases. Nearly 45% of patients have variants associated with known diseases but the unsolved cases remain a conundrum. Moreover, causative mutations can be difficult to pinpoint because variants frequently map to genes with no previous disease associations and, often, only one or a few patients with variants in the same gene are identified. Model organisms, such as Drosophila , can help to identify and characterize these new disease-causing genes. Importantly, Drosophila allow quick and sophisticated genetic manipulations, permit functional testing of human variants, enable the characterization of pathogenic mechanisms and are amenable to drug tests. In this Spotlight, focusing on microcephaly as a case study, we highlight how studies of human genes in Drosophila have aided our understanding of human genetic disorders, allowing the identification of new genes in well-established signaling pathways.

ABSTRACT Regenerative therapies, including both gene and cellular therapies, aim to induce regeneration of cells, tissues and organs and restore their functions. In this short Spotlight, we summarize the latest advances in cellular therapies using pluripotent stem cells (PSCs), highlighting the current status of clinical trials using induced (i)PSC-derived cells. We also discuss the different cellular products that might be used in clinical studies, and consider safety issues and other challenges in iPSC-based cell therapy.

ABSTRACT Mutations play a crucial role in evolution as they provide the genetic variation that allows evolutionary change. Although some mutations in regulatory elements or coding regions can be beneficial, a large number of them disrupt gene function and reduce fitness. Organisms utilize several mechanisms to compensate for the damaging consequences of genetic perturbations. One such mechanism is the recently identified process of transcriptional adaptation (TA): during this event, mutations that cause mutant mRNA degradation trigger the transcriptional modulation of so-called adapting genes. In some cases, for example when one (or more) of the upregulated genes is functionally redundant with the mutated gene, this process compensates for the loss of the mutated gene's product. Notably, unlike other mechanisms underlying genetic robustness, TA is not triggered by the loss of protein function, an observation that has prompted studies into the machinery of TA and the contexts in which it functions. Here, we review the discovery and current understanding of TA, and discuss how its main features appear to be conserved across species. In light of these findings, we also speculate on the importance of TA in the context of human disease, and provide some recommendations for genome-editing strategies that should be more effective.

ABSTRACT Developmental biologists rely on genetics-based approaches to understand the origins of congenital abnormalities. Recent advancements in genomics have made it easier than ever to investigate the relationship between genes and disease. However, nonsyndromic birth defects often exhibit non-Mendelian inheritance, incomplete penetrance or variable expressivity. The discordance between genotype and phenotype indicates that extrinsic factors frequently impact the severity of genetic disorders and vice versa. Overlooking gene-environment interactions in birth defect etiology limits our ability to identify and eliminate avoidable risks. We present mouse models of sonic hedgehog signaling and craniofacial malformations to illustrate both the importance of and current challenges in resolving gene-environment interactions in birth defects. We then prescribe approaches for overcoming these challenges, including use of genetically tractable and environmentally responsive in vitro systems. Combining emerging technologies with molecular genetics and traditional animal models promises to advance our understanding of birth defect etiology and improve the identification and protection of vulnerable populations.

ABSTRACT Understanding the etiology of congenital disorders requires interdisciplinary research and close collaborations between clinicians, geneticists and developmental biologists. The pace of gene discovery has quickened due to advances in sequencing technology, resulting in a wealth of publicly available sequence data but also a gap between gene discovery and crucial mechanistic insights provided by studies in model systems. In this Spotlight, I highlight the opportunities for developmental biologists to engage with human geneticists and genetic resources to advance the study of congenital disorders.

ABSTRACT Developmental biologists have frequently pushed the frontiers of modern biomedical research. From the discovery and characterization of novel signal transduction pathways to exploring the molecular underpinnings of genetic inheritance, transcription, the cell cycle, cell death and stem cell biology, studies of metazoan development have historically opened new fields of study and consistently revealed previously unforeseen avenues of clinical therapies. From this perspective, it is not surprising that our community is now an integral part of the current renaissance in metabolic research. Amidst the global rise in metabolic syndrome, the discovery of novel signaling roles for metabolites, and the increasing links between altered metabolism and many human diseases, we as developmental biologists can contribute skills and expertise that are uniquely suited for investigating the mechanisms underpinning human metabolic health and disease. Here, we summarize the opportunities and challenges that our community faces, and discuss how developmental biologists can make unique and valuable contributions to the field of metabolism and physiology.

ABSTRACT How much evolutionary change in development do we expect? In this Spotlight, we argue that, as developmental biologists, we are in a prime position to contribute to the definition of a null hypothesis for developmental evolution: in other words, a hypothesis for how much developmental evolution we expect to observe over time. Today, we have access to an unprecedented array of developmental data from across the tree of life. Using these data, we can now consider development in the light of evolution, and vice versa, more deeply than ever before. As we do this, we may need to re-examine previous assumptions that appeared to serve us well when data points were fewer. Specifically, we think it is important to challenge assumptions that change is very rare for all developmental traits, especially if this assumption is used to sustain an erroneous view that evolution always optimizes adaptive traits toward increasing complexity.

ABSTRACT Organoids are three-dimensional multicellular structures grown in vitro from stem cells and which recapitulate some organ function. They are derivatives of living tissue that can be stored in biobanks for a multitude of research purposes. Biobank research on organoids derived from patients is highly promising for precision medicine, which aims to target treatment to individual patients. The dominant approach for protecting the interests of biobank participants emphasizes broad consent in combination with privacy protection and ex ante (predictive) ethics review. In this paradigm, participants are positioned as passive donors; however, organoid biobanking for precision medicine purposes raises challenges that we believe cannot be adequately addressed without more ongoing involvement of patient-participants. In this Spotlight, we argue why a shift from passive donation towards more active involvement is particularly crucial for biobank research on organoids aimed at precision medicine, and suggest some approaches appropriate to this context.

ABSTRACT Single cell RNA-sequencing (scRNA-seq) technology has matured to the point that it is possible to generate large single cell atlases of developing mouse embryos. These atlases allow the dissection of developmental cell lineages and molecular changes during embryogenesis. When coupled with single cell technologies for profiling the chromatin landscape, epigenome, proteome and metabolome, and spatial tissue organisation, these scRNA-seq approaches can now collect a large volume of multi-omic data about mouse embryogenesis. In addition, advances in computational techniques have enabled the inference of developmental lineages of differentiating cells, even without explicitly introduced genetic markers. This Spotlight discusses recent advent of single cell experimental and computational methods, and key insights from applying these methods to the study of mouse embryonic development. We highlight challenges in analysing and interpreting these data to complement and expand our knowledge from traditional developmental biology studies in relation to cell identity, diversity and lineage differentiation.

ABSTRACT Snails, earthworms and flatworms are remarkably different animals, but they all exhibit a very similar mode of early embryogenesis: spiral cleavage. This is one of the most widespread developmental programs in animals, probably ancestral to almost half of the animal phyla, and therefore its study is essential for understanding animal development and evolution. However, our knowledge of spiral cleavage is still in its infancy. Recent technical and conceptual advances, such as the establishment of genome editing and improved phylogenetic resolution, are paving the way for a fresher and deeper look into this fascinating early cleavage mode.

ABSTRACT Two phrases attributed to Lewis Wolpert – ‘positional information’ and ‘The French Flag Model’ – have become so intertwined that they are now used almost interchangeably. Here, I argue that this represents an unfortunate oversimplification of Wolpert's ideas that arose gradually in the developmental biology community, some significant time after his key papers were published. In contrast to common belief, Wolpert did not use the phrase French Flag ‘Model’ but instead introduced the French Flag ‘Problem’. This famous metaphor was not a proposal of how patterning works, but rather an abstraction of the question to be addressed. More specifically, the French flag metaphor was an attempt to de-couple the problem from the multiple possible models that could solve it. In this spirit, Wolpert's first article on this topic also proposed (in addition to the well-known gradient model) an alternative solution to the French Flag Problem that was self-organising and had no gradients, and in which each cell ‘cannot compute where it is in the system’, i.e. there is no positional information. I discuss the history and evolution of these terms, and how they influence the way we study patterning.