A New Paradigm for Pandemic Preparedness.

Purpose Of Review: Preparing for pandemics requires a degree of interdisciplinary work that is challenging under the current paradigm. This review summarizes the challenges faced by the field of pandemic science and proposes how to address them.

Recent Findings: The structure of current siloed systems of research organizations hinders effective interdisciplinary pandemic research.

Autonomous and non-cell autonomous role of cilia in structural birth defects in mice.

Ciliopathies are associated with wide spectrum of structural birth defects (SBDs), indicating important roles for cilia in development. Here, we provide novel insights into the temporospatial requirement for cilia in SBDs arising from deficiency in Ift140, an intraflagellar transport (IFT) protein regulating ciliogenesis. Ift140-deficient mice exhibit cilia defects accompanied by wide spectrum of SBDs including macrostomia (craniofacial defects), exencephaly, body wall defects, tracheoesophageal fistula (TEF), randomized heart looping, congenital heart defects (CHDs), lung hypoplasia, renal anomalies, and polydactyly.

Joint multi-ancestry and admixed GWAS reveals the complex genetics behind human cranial vault shape.

The cranial vault in humans is highly variable, clinically relevant, and heritable, yet its genetic architecture remains poorly understood. Here, we conduct a joint multi-ancestry and admixed multivariate genome-wide association study on 3D cranial vault shape extracted from magnetic resonance images of 6772 children from the ABCD study cohort yielding 30 genome-wide significant loci. Follow-up analyses indicate that these loci overlap with genomic risk loci for sagittal craniosynostosis, show elevated activity cranial neural crest cells, are enriched for processes related to skeletal development, and are shared with the face and brain.

Autonomous and non-cell autonomous etiology of ciliopathy associated structural birth defects.

Ciliopathies are associated with wide spectrum of structural birth defects (SBD), indicating important roles for cilia in development. Here we provide novel insights into the temporospatial requirement for cilia in SBDs arising from deficiency in , an intraflagellar transport protein regulating ciliogenesis. deficient mice exhibit cilia defects accompanied by wide spectrum of SBDs including macrostomia (craniofacial defects), exencephaly, body wall defects, tracheoesophageal fistula, randomized heart looping, congenital heart defects (CHD), lung hypoplasia, renal anomalies, and polydactyly.

× Interaction Revealed by Genome-Wide vQTL Analysis of Human Facial Traits.

The human face is a highly complex and variable structure resulting from the intricate coordination of numerous genetic and non-genetic factors. Hundreds of genomic loci impacting quantitative facial features have been identified. While these associations have been shown to influence morphology by altering the mean size and shape of facial measures, their effect on trait variance remains unclear.

Chondrocyte Polarity During Endochondral Ossification Requires Protein-Protein Interactions Between Prickle1 and Dishevelled2/3.

The expansion and growth of the endochondral skeleton requires organized cell behaviors that control chondrocyte maturation and oriented division. In other organs, these processes are accomplished through Wnt/planar cell polarity (Wnt/PCP) signaling pathway and require the protein-protein interactions of core components including Prickle1 (PK1) and Dishevelled (DVL). To determine the function of Wnt/PCP signaling in endochondral ossification of the cranial base and limb, we utilized the Prickle1 (Pk1 ) mouse line.

Finding the , a New Mouse Model of Midfacial Clefting.

Human midfacial clefting is a rare subset of orofacial clefting and in severe cases, the cleft separates the nostrils splitting the nose into two independent structures. To begin to understand the morphological and genetic causes of midfacial clefting we recovered the mouse line. embryos develop a complete midfacial cleft through the lip, and snout closely modelling human midfacial clefting.

Localization of , , , , and Expression in the Developing Retina, Muscle, and Sclera of the Embryonic Mouse Eye.

Optic development involves sequential interactions between several different tissue types, including the overlying ectoderm, adjacent mesoderm, and neural crest mesenchyme and the neuroectoderm. In an ongoing expression screen, we identified that , , , , and are expressed in unique cell types in and around the developing eye. , , and are transcription factors, is a calcium binding protein and is a neurotransmitter.

Prickle1 regulates differentiation of frontal bone osteoblasts.

Enlarged fontanelles and smaller frontal bones result in a mechanically compromised skull. Both phenotypes could develop from defective migration and differentiation of osteoblasts in the skull bone primordia. The Wnt/Planar cell polarity (Wnt/PCP) signaling pathway regulates cell migration and movement in other tissues and led us to test the role of Prickle1, a core component of the Wnt/PCP pathway, in the skull.

A six-gene expression toolbox for the glands, epithelium and chondrocytes in the mouse nasal cavity.

The nose is the central feature of the amniote face. In adults, the nose is a structurally and functionally complex organ that consists of bone, cartilage, glands and ducts. In an ongoing expression screen in our lab, we found several novel markers for specific tissues in the nasal region.

Growth factor signaling alters the morphology of the zebrafish ethmoid plate.

Craniofacial development relies on coordinated tissue interactions that allow for patterning and growth of the face. We know a priori that the Wingless, fibroblast growth factor, Hedgehog and transforming growth factor-beta growth factor signaling pathways are required for the development of the face, but how they contribute to the shape of the face is largely untested. Here, we test how each signaling pathway contributes to the overall morphology of the zebrafish anterior neurocranium.

Prickle1 mutation causes planar cell polarity and directional cell migration defects associated with cardiac outflow tract anomalies and other structural birth defects.

Planar cell polarity (PCP) is controlled by a conserved pathway that regulates directional cell behavior. Here, we show that mutant mice harboring a newly described mutation termed Beetlejuice (Bj) in Prickle1 (Pk1), a PCP component, exhibit developmental phenotypes involving cell polarity defects, including skeletal, cochlear and congenital cardiac anomalies. Bj mutants die neonatally with cardiac outflow tract (OFT) malalignment.

Accelerated enamel mineralization in Dspp mutant mice.

Dentin sialophosphoprotein (DSPP) is one of the major non-collagenous proteins present in dentin, cementum and alveolar bone; it is also transiently expressed by ameloblasts. In humans many mutations have been found in DSPP and are associated with two autosomal-dominant genetic diseases - dentinogenesis imperfecta II (DGI-II) and dentin dysplasia (DD). Both disorders result in the development of hypomineralized and mechanically compromised teeth.

Fuz mutant mice reveal shared mechanisms between ciliopathies and FGF-related syndromes.

Ciliopathies are a broad class of human disorders with craniofacial dysmorphology as a common feature. Among these is high arched palate, a condition that affects speech and quality of life. Using the ciliopathic Fuz mutant mouse, we find that high arched palate does not, as commonly suggested, arise from midface hypoplasia.

Novel reporter alleles of GSK-3α and GSK-3β.

Glycogen Synthase Kinase 3 (GSK-3) is a key player in development, physiology and disease. Because of this, GSK-3 inhibitors are increasingly being explored for a variety of applications. In addition most analyses focus on GSK-3β and overlook the closely related protein GSK-3α.

Neural crest origin of olfactory ensheathing glia.

Olfactory ensheathing cells (OECs) are a unique class of glial cells with exceptional translational potential because of their ability to support axon regeneration in the central nervous system. Although OECs are similar in many ways to immature and nonmyelinating Schwann cells, and can myelinate large-diameter axons indistinguishably from myelination by Schwann cells, current dogma holds that OECs arise from the olfactory epithelium. Here, using fate-mapping techniques in chicken embryos and genetic lineage tracing in mice, we show that OECs in fact originate from the neural crest and hence share a common developmental heritage with Schwann cells.

New directions in craniofacial morphogenesis.

The vertebrate head is an extremely complicated structure: development of the head requires tissue-tissue interactions between derivates of all the germ layers and coordinated morphogenetic movements in three dimensions. In this review, we highlight a number of recent embryological studies, using chicken, frog, zebrafish and mouse, which have identified crucial signaling centers in the embryonic face. These studies demonstrate how small variations in growth factor signaling can lead to a diversity of phenotypic outcomes.

The planar cell polarity effector Fuz is essential for targeted membrane trafficking, ciliogenesis and mouse embryonic development.

The planar cell polarity (PCP) signalling pathway is essential for embryonic development because it governs diverse cellular behaviours, and 'core PCP' proteins, such as Dishevelled and Frizzled, have been extensively characterized. By contrast, the 'PCP effector' proteins, such as Intu and Fuz, remain largely unstudied. These proteins are essential for PCP signalling, but they have never been investigated in mammals and their cell biological activities remain entirely unknown.

Novel skeletogenic patterning roles for the olfactory pit.

The position of the olfactory placodes suggests that these epithelial thickenings might provide morphogenetic information to the adjacent facial mesenchyme. To test this, we performed in ovo manipulations of the nasal placode in the avian embryo. Extirpation of placodal epithelium or placement of barriers on the lateral side of the placode revealed that the main influence is on the lateral nasal, not the frontonasal, mesenchyme.

FGF signals from the nasal pit are necessary for normal facial morphogenesis.

Fibroblast growth factors (FGFs) are required for brain, pharyngeal arch, suture and neural crest cell development and mutations in the FGF receptors have been linked to human craniofacial malformations. To study the functions of FGF during facial morphogenesis we locally perturb FGF signalling in the avian facial prominences with FGFR antagonists, foil barriers and FGF2 protein. We tested 4 positions with antagonist-soaked beads but only one of these induced a facial defect.