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.

Regeneration “Functional significance of earthworm clitellum in regulating the various biological aspects of cell survival and regeneration” by Jackson Durairaj Selvan Christyraj, Ashwin Barath Vaidhyalingham, Chandini Sengupta, Kamarajan Rajagopalan, Kayalvizhi Vadivelu, Nandha Kumar Suresh, and Bharathi Venkatachalam Dev Dyn 254.3, pp. 212–221, https://doi.org/10.1002/dvdy.751. Earthworms exhibit a remarkable ability to rapidly heal and completely regenerate within a short period of time. Earthworms are therefore an ideal model for studying the mechanisms that regulate stem cell biology and regeneration. Over 7000 different species of earthworms have been identified and described, and this review describes new insights into the functions of the clitellum, which is a glandular structure that sits near the head. During epimorphosis, undifferentiated stem cells that reside in the clitellar region divide and form a blastema, which then develops into new tissue. In contrast, during morphallaxis, in which regeneration occurs without the formation of a blastema, it is thought that cells in the clitellum undergo trans-differentiation. Either way, the clitellum is regarded as a stem cell reservoir that regulates regeneration. However, in addition to regeneration, the clitellum plays essential roles in reproduction, organogenesis, and aging.

Cardiovascular Biology “Modulation of mechanosensitive genes during embryonic aortic arch development” by Hummaira Banu Siddiqui, Tansu Golcez, Merve Çelik, Börteçine Sevgin, Mervenur Çoban, İlke Süder, Özen Kaya, Nesrin Özören, and Kerem Pekkan Dev Dyn 254.3, pp. 222–239, https://doi.org/10.1002/dvdy.728. The embryonic aortic arches are dynamic vascular structures that develop into the great arteries of the cardiovascular system. The extracellular matrix is known to play important roles in aortic arch and vascular morphogenesis, and computational and other types of modeling have linked mechanical properties such as blood pressure, wall shear stress, outflow tract orientation, and blood flow, to the developmental morphology of the aortic arches. Developmental malformations of the aortic arches manifest as congenital heart defects. In this study, the authors modulated the activity of genes associated with wall shear stress such as TGFβ3 and MMP2. TGFβ3 knockdown results in decreases in collagen and elastin density, with corresponding alterations in hemodynamics and blood pressure, that lead to detrimental effects on lumen diameter and the accumulation of blood cells. Knockdown of MMP2 increases COL-III expression and the diameter of the aortic arches significantly, which affects tissue remodeling, cardiac cushion cell migration, and blood vessel maturation. These perturbations of two major mechanosensitive networks lend support to the idea that cardiac gene regulation is mechanically controlled during cardiovascular development.

Craniofacial Biology “Expression analysis of genes including Zfhx4 in mice and zebrafish reveals a temporospatial conserved molecular basis underlying craniofacial development” by Shujie Liu, Lin Xu, Makoto Kashima, Rika Narumi, Yoshifumi Takahata, Eriko Nakamura, Hirotoshi Shibuya, Masaru Tamura, Yuki Shida, Toshihiro Inubushi, Yuko Nukada, Masaaki Miyazawa, Kenji Hata, Riko Nishimura, Takashi Yamashiro, Junichi Tasaki, and Hiroshi Kurosaka Dev Dyn 254.3, pp. 257–271, https://doi.org/10.1002/dvdy.740. Mice and zebrafish are frequently used to model human disorders such as congenital craniofacial defects, including orofacial clefts. Although palatogenesis in zebrafish is morphologically distinct from that in mammals, neural crest cells are important contributors to the process in both species and their development depends on common or conserved molecular networks. In this study, the authors initially focused on Sox9 and identified 86 genes exhibiting similar expression dynamics in mice and zebrafish. They then focused on Zfhx4/zfhx4 and its expression and function during craniofacial development, especially in the upper jaw. Perturbation of Zfhx4/zfhx4 results in disruption of palatal shelf development in mice, and distortion of the ethmoid plate in zebrafish, respectively. The ethmoid plate in zebrafish has been considered equivalent to the primary palate in mammals, and zfhx4 appears to be required for neural crest cell migration and facial primordia formation in zebrafish. These results provide further evidence for the similarities in the craniofacial development between zebrafish and mice, and shed new light on orofacial clefts in humans, some of which have recently been associated with pathogenic variants in the human homolog ZFHX4. Thus, elucidating the shared mechanisms of craniofacial development between disease models is crucial to understanding the underlying mechanisms of phenotypes in individual species.

A companion study explores gene–environment interactions in the pathogenesis of craniofacial disorders. “foxe1 mutant zebrafish show indications of a hypothyroid phenotype and increased sensitivity to ethanol for craniofacial malformations” by Sophie Raterman, Frank Wagener, Jan Zethof, Vincent Cuijpers, Peter Klaren, Juriaan Metz, and Johannes Von den Hoff Dev Dyn 254.3, pp. 240–256, https://doi.org/10.1002/dvdy.745. The majority of birth defects are considered multifactorial in origin, and the incomplete penetrance of Mendelian disorders is quite common, possibly as a result of incomplete penetrance, variable expressivity, and even gene–environment interactions can all contribute to the discordance between genotype and phenotype. Environmental factors such as drug use, smoking, and drinking during pregnancy are well known to increase the risk of congenital malformations. FOXE1 is a transcription factor important for proper palate formation and thyroid morphogenesis, and variants in FOXE1 in humans lead to Bamforth–Lazarus syndrome. This study explores the effect of ethanol exposure on the risk of developing craniofacial malformations in foxe1 mutant zebrafish, which can be used to model Bamforth–Lazarus syndrome. Indeed, ethanol-exposed foxe1 mutants exhibit an increased incidence of developmental malformations, illustrating the clear interaction between foxe1 and ethanol. This approach can now be used for further investigation of the role of FOXE1 in thyroid development and palatogenesis to screen for possible gene–environment interactions in the etiology of craniofacial malformations.

Gastrointestinal Organogenesis “BMP signaling pathway member expression is enriched in enteric neural progenitors and required for zebrafish enteric nervous system development” by Joshua Moore, Rodrigo Moreno-Campos, Arielle Noah, Eileen Singleton, and Rosa Uribe Dev Dyn 254.3, pp. 272–287, https://doi.org/10.1002/dvdy.737. The enteric nervous system is a major component of the autonomic nervous system and controls the intrinsic functions of the gastrointestinal tract. Often referred to as “the second brain,” the enteric nervous system is comprised of hundreds of millions of neurons, arranged in functional units called ganglia. The enteric nervous system is primarily derived from neural crest cells, which are born in the neural tube, but then migrate into the primitive gut tube, and through a balance between proliferation, migration, and differentiation, they populate the entirety of the gastrointestinal tract. This study explores the intrinsic and extrinsic factors that regulated proper enteric nervous system and gastrointestinal development and function. Through transcriptomic, gene expression, immunohistochemical analysis, and chemical attenuation, the authors identified a time-dependent role for bone morphogenetic protein (BMP) in the maintenance of phox2bb+ enteric progenitor numbers or their time of differentiation of the progenitor pool. More specifically, BMP5 was shown to be critical for colonization of the gastrointestinal tract, since in its absence, the number of phox2bb+ enteric progenitor numbers was considerably reduced. Impaired proliferation, migration, or differentiation of neural crest cells can result in disorders of gastrointestinal development, such as Hirschsprung disease.