Phenotyping the brain, the face, and their genetic interaction over development

The development of the brain and the face is intimately coordinated through a continuous physical and molecular interaction during morphogenesis. Understanding how dynamic spatio-temporal regulation of gene expression patterns guide this process is crucial to reveal mechanisms that may have contributed to human evolution

The role of networks to overcome large-scale challenges in tomography : the non-clinical tomography users research network

Our ability to visualize and quantify the internal structures of objects via computed tomography (CT) has fundamentally transformed science. As tomographic tools have become more broadly accessible, researchers across diverse disciplines have embraced the ability to investigate the 3D structure-function relationships of an enormous array of items. Whether studying organismal biology, animal models for human health, iterative manufacturing techniques, experimental medical devices, engineering structures, geological and planetary samples, prehistoric artifacts, or fossilized organisms, computed tomography has led to extensive methodological and basic sciences advances and is now a core element in science, technology, engineering, and mathematics (STEM) research and outreach toolkits. Tomorrow's scientific progress is built upon today's innovations. In our data-rich world, this requires access not only to publications but also to supporting data. Reliance on proprietary technologies, combined with the varied objectives of diverse research groups, has resulted in a fragmented tomography-imaging landscape, one that is functional at the individual lab level yet lacks the standardization needed to support efficient and equitable exchange and reuse of data. Developing standards and pipelines for the creation of new and future data, which can also be applied to existing datasets is a challenge that becomes increasingly difficult as the amount and diversity of legacy data grows. Global networks of CT users have proved an effective approach to addressing this kind of multifaceted challenge across a range of fields. Here we describe ongoing efforts to address barriers to recently proposed FAIR (Findability, Accessibility, Interoperability, Reuse) and open science principles by assembling interested parties from research and education communities, industry, publishers, and data repositories to approach these issues jointly in a focused, efficient, and practical way. By outlining the benefits of networks, generally, and drawing on examples from efforts by the Non-Clinical Tomography Users Research Network (NoCTURN), specifically, we illustrate how standardization of data and metadata for reuse can foster interdisciplinary collaborations and create new opportunities for future-looking, large-scale data initiatives

Phenotypes, Developmental Basis, and Genetics of Pierre Robin Complex

The phenotype currently accepted as Pierre Robin syndrome/sequence/anomalad/complex (PR) is characterized by mandibular dysmorphology, glossoptosis, respiratory obstruction, and in some cases, cleft palate. A causative sequence of developmental events is hypothesized for PR, but few clear causal relationships between discovered genetic variants, dysregulated gene expression, precise cellular processes, pathogenesis, and PR-associated anomalies are documented. This review presents the current understanding of PR phenotypes, the proposed pathogenetic processes underlying them, select genes associated with PR, and available animal models that could be used to better understand the genetic basis and phenotypic variation of PR

Quantification of Gene expression patterns to reveal the origins of abnormal morphogenesis

The earliest developmental origins of dysmorphologies are poorly understood in many congenital diseases. They often remain elusive because the first signs of genetic misregulation may initiate as subtle changes in gene expression, which are hard to detect and can be obscured later in development by secondary effects. Here, we develop a method to trace back the origins of phenotypic abnormalities by accurately quantifying the 3D spatial distribution of gene expression domains in developing organs. By applying Geometric Morphometrics to 3D gene expression data obtained by Optical Projection Tomography, we determined that our approach is sensitive enough to find regulatory abnormalities that have never been detected previously. We identified subtle but significant differences in the gene expression of a downstream target of a Fgfr2 mutation associated with Apert syndrome, demonstrating that these mouse models can further our understanding of limb defects in the human condition. Our method can be applied to different organ systems and models to investigate the etiology of malformations

Assessing Gene Expression Patterns in Mouse Models to Test Hypotheses About Human Head Evolution

Continuous fossil discoveries and recent analysis of genomic data are revealing that anatomically modern traits evolved following a complex evolutionary path. Our current understanding of human evolution considers that the skull likely evolved as a mosaic of correlated traits whose development is in turn integrated with other organs, such as the brain. However, we still know little about the complexity of the genetic networks supervising these processes and the developmental mechanisms underlying observed patterns of morphological evolution. To further understand the integrated evolution of the human skull and brain, it is crucial to characterize the gene expression patterns that provide detailed instructions to organize cell behavior, tissue growth, and organ patterning and to investigate how development translates genetic variation into phenotypic variation. We propose that developmental biology analyses using mouse models can enable the experimental test of hypotheses about how craniofacial morphological diversification occurred across the human lineage. Here, we combine molecular (Whole-Mount in situ Hybridization), 3D imaging (Optical Projection Tomography), and morphometric techniques to assess changes in the space, time, and intensity of gene expression patterns during embryonic development. We used Fgfr2+/P253R Apert syndrome mouse models, in which an Fgfr2 mutation is associated with midfacial hypoplasia, brachycephaly, and macrocephaly. These pathological phenotypes provide a practical model of processes similar to those involved in the evolution of a large globular braincase and a small, retracted face in modern humans. We compared the expression patterns of two downstream targets of Fgfr2, Dusp6 and Hand2, that are relevant for brain and craniofacial development, in 25 mice carrying the Fgfr2 mutation and 27 littermates collected between E10.5 and E11.5. Qualitative comparisons revealed that both genes are co-expressed in the brain and face with variable intensity depending on developmental time and genotype. Results suggest that the FGF signaling pathway participates in brain and face morphogenesis and that changes in the location and timing of gene expression can induce correlated changes in brain and craniofacial systems. This supports the hypothesis that facial retraction and encephalization likely evolved as direct and correlated responses to common signaling pathways. We are testing high throughput methods to produce objective quantifications of gene expression patterns that can be used in future analyses to reveal the complex genotype-phenotype correspondence in the evolution of modern human traits