Editorial highlights

Every organism is a model organism for understanding development, evolution, disease, and regeneration, and we have only begun to scratch the surface of the interdisciplinary genetic, molecular, cellular, and developmental mechanisms that regulate these biological processes. These “Highlights” denote exciting advances recently reported in Developmental Dynamics that illustrate the complex dynamics of developmental biology.

Placental Influences on Craniofacial and Brain Development. “A head start: The relationship of placental factors to craniofacial and brain development” by Annemarie Carver, Martine Dunnwald, and Hanna Stevens.¹ The placenta produces and helps deliver hormones, nutrients, and oxygen to offspring in utero. Its impact on neurodevelopment and neurodevelopmental disorders, known as neuroplacentology, is an emerging field of growing scientific and research interest. Neurodevelopment is also highly coordinated with craniofacial development, as is the co-occurrence of neurodevelopmental disorders and craniofacial disorders, which has led to the adage, “the face predicts the brain, and the brain predicts the face.” This review discusses the role of placental hormone production and nutrient delivery during the development of the fetal head with a particular emphasis on hormones such as IGF1, GH, and PRL, nutrients such as calcium, sulfate, and vitamin D, and their respective signaling pathways. Further investigation into placental-specific mechanisms influencing the development of the fetal head offers the potential to better understand and possibly even prevent many common childhood health problems.

Morphogenesis of the Neural Tube. “An analysis of contractile and protrusive cell behaviors at the superficial surface of the zebrafish neural plate” by Claudio Araya, Raegan Boekemeyer, Francesca Farlie, Lauren Moon, Freshta Darwish, Chris Rookyard, Leanne Allison, Gema Vizcay-Barrena, Roland Fleck, Millaray Aranda, Masa Tada, and Jonathan Clarke.² The neural tube is the embryonic precursor of the brain and spinal cord. It emerges from the neuroepithelium or neural plate, and accumulating evidence shows that convergent and extension movements and apical constriction are the two dominant cell behaviors responsible for shaping the neural plate into a neural tube. Although the zebrafish (a teleost, ray-finned fish) neural plate has a different cytoarchitecture compared to other vertebrates, it still uses several morphogenetic mechanisms conserved with other vertebrates, such as non-canonical Wnt/planar cell polarity (PCP) signaling regulation of convergence-extension, through cell intercalation and axial elongation. This study used high spatial and rapid temporal in vivo imaging to define the cell surface dynamics governing zebrafish neural plate convergence and internalization, and uncovered a role for Cadherin-based cell adhesion in the protrusive activity of neural plate cells.

Environmental Impact on Development. “Loss of the epithelial transcription factor grhl3 leads to variably penetrant developmental phenotypes in zebrafish” by Nishanthi Mathiyalagan, Travis Johnson, Zachary Di Pastena, Jarrad Fuller, Lee Miles and Sebastian Dworkin.³ Grainyhead (grh) transcription factors have been well described as key epithelial regulators of wound healing, neural tube closure, craniofacial formation, epidermal cancer, and skin barrier homeostasis. Despite about 700 million years of functional genetic conservation, this study reports an unexpected change in the phenotype of a zebrafish grhl3 loss-of-function knockout upon transfer to a new zebrafish housing facility. The impact of gene–environment interactions on development and disease is well known but poorly understood. However, environmental influences are significantly under-appreciated under laboratory conditions because animal housing facilities are not typically designed to robustly test environmental variability. The authors subsequently identified a putative novel downstream target gene that significantly reduces grhl3^−/− embryo mortality and substantially ameliorates overall phenotypic severity in this model. This work provides the impetus to investigate whether bioactive factors may similarly improve clinical outcomes for patients with GRHL3-mediated developmental defects such as spina bifida or cleft palate.

Vertebrae and Intervertebral Disk Development. “Active cell proliferation contributes to the enlargement of the nascent nucleus pulposus” by Rose Long, Changhee Lee, and Clifford J. Tabin.⁴ The spinal column consists of alternating vertebral bodies and intervertebral discs. The intervertebral disks are cushions of fibrocartilage that provide flexibility to the spine, while also acting as shock absorbers. Each intervertebral disc has two structural domains, a ring of somite-derived fibrous tissue, the annulus fibrosus, which encircles an inner, notochord-derived tissue, the nucleus pulposus. But how the notochord resolves into the nucleus pulposus is unclear. The current model of notochordal segmentation suggests that swelling through the formation and maturation of the vertebrate cartilage squeezes the notochord cells from the vertebra. This study, however, reveals that Collagen 10, a marker of hypertrophy, is expressed in the forming vertebrae after the notochord is already fully excluded from the vertebra. Furthermore, it is only after the exclusion of the notochord that the vertebrae dramatically expand in concert with a significant decrease in density. Thus, the enlargement of the nucleus pulposus occurs before the vertebra undergoes hypertrophy, and the bulk of the nucleus pulposus is derived from accelerated proliferation within the notochord-derived nucleus pulposus itself.

Human Stem Cell Models of Congenital Disorders. “Human stem cell model of neural crest cell differentiation reveals a requirement of SF3B4 in survival, maintenance, and differentiation” by Casey Griffin and Jean-Pierre Saint-Jeannet.⁵ RNA splicing removes non-coding genetic segments, or introns, from pre-messenger RNA such that the remaining protein coding genetic segments, or exons, can be joined together as a mature messenger RNA, the template used for protein synthesis. This process facilitates the generation of protein diversity and is performed by the spliceosome. Interestingly, while the spliceosome is active in all cell types, variants in genes encoding the proteins that make up the spliceosome result in diseases known as spliceosomopathies, which are characterized by tissue-specific phenotypes. In vitro modeling is a powerful and rapid screening approach to investigate the etiology and pathogenic mechanisms driving human congenital conditions. In this study, the authors used human embryonic stem cells to model Nager and Rodriguez syndromes, two craniofacial disorders caused by pathogenic variants in SF3B4, a core component of the spliceosome. Knockdown of SF3B4 unveiled its central roles in the survival, maintenance, and differentiation of neural crest cells, which are the precursors of most of the bone, cartilage, and connective tissue in the human face, underscoring the mechanistic pathogenesis of Nager and Rodriguez syndromes.