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.

Signaling in Organogenesis. “The synergistic link between sonic hedgehog signaling pathway and gut–lung axis: Its influential role toward chronic obstructive pulmonary disease progression” by Nidhi Mahajan, Vishal Chopra, Kranti Garg, and Siddharth Sharma.¹ Chronic obstructive pulmonary disease (COPD) is a progressive heterogeneous lung disease characterized by obstructive airflow due to the abnormalities of bronchitis and alveoli. The etiology and pathogenesis of COPD is however, poorly understood due to the complexity of the multitude of mechanisms involved, including gene–environment interactions, abnormal lung development, lung dysfunction, psychological distress, muscle dysfunction, and other comorbid diseases. Smoking is a key driver of the pathogenesis of COPD via the aberrant activation of SHH signaling which regulates epithelial and mesenchymal transition (EMT) in the airways. This review describes the role of SHH signaling during lung development and its dysregulation in association with the clinical features of COPD pathogenesis. The authors also link the effects of nicotine on SHH signaling and discuss a surprising link between microbiota and the gut–lung axis on COPD pathogenesis.

Tooth Development. “Endocytosis mediated by megalin and cubilin is involved in enamel development” by Aijia Wang, Yangxi Chen, Xinye Zhang, Ming Liu, Shumin Liu, Renata Kozyraki, and Zhi Chen.² Amelogenesis is the process of forming tooth enamel, a highly mineralized tissue. Amelogenesis consists of a secretory stage and maturation stage, and endocytosis of enamel matrix proteins by ameloblasts during the maturation stage is critical for the mineralization of enamel. This study set out to discover the receptors that mediate endocytosis of enamel matrix proteins. Megalin and cubilin, two known endocytic receptors, are expressed by ameloblasts in mouse incisors and molars during the secretory and maturation stages of amelogenesis, but megalin was more specifically localized to the vesicle structures in an ameloblast lineage cell line. Inhibition of megalin and cubilin by receptor-associated protein (RAP) resulted in reduced the absorption of amelogenin, illustrating their key roles in amelogenesis. Megalin and cubilin function in the recycling of amelogenin during the maturation stage of amelogenesis and may contribute to the subsequent mineralization of mature enamel.

WNT Signaling and the Evolution of Multicellularity. “β-Catenin localization in the ctenophore Mnemiopsis leidyi suggests an ancestral role in cell adhesion and nuclear function” by Brian Walters, Lucas Guttieres, Mayline Goëb, Stanley Marjenberg, Mark Martindale, and Athula Wikramanayake.³ The origin of multicellularity was a major evolutionary event that transformed our single-celled ancestors into complex organisms composed of multiple, specialized cell types. But what fundamental mechanisms enabled this transition to occur sin subsequently underpin the evolution and diversification of animals and plants throughout nature. Cell–cell adhesion, cell–extracellular matrix interactions, cell–cell communication, and cell fate specification among many other cellular processes were involved, and WNT/β-catenin signaling is a critical regulator of many of these processes. In this study, the authors report the generation of affinity-purified rabbit polyclonal antibodies targeting the ctenophore Mnemiopsis leidyi β-catenin protein and then use it to determine the subcellular distribution of the protein during early ctenophore embryo development. This study presents evidence of nuclear restriction of β-catenin protein at the oral pole ctenophore embryos during gastrulation and enrichment at cell–cell interfaces. The localization of β-catenin suggests that this protein had an ancestral role in cell adhesion and nuclear functions as well. Thus WNT/β-catenin signaling may have facilitated cellular cooperation through the partitioning of cell–cell adhesion, cell–extracellular matrix interactions, cell–cell communication, and cell fate specification in the metazoan last common ancestor.

Muscle Development. “A novel transgenic reporter of extracellular acidification in zebrafish elucidates skeletal muscle T-tubule pH regulation” by Leif Neitzel, Maya Silver, Aaron Wasserman, Samantha Rea, Charles Hong, and Charles Williams.⁴ Extracellular protons (H+) are gaining recognition as critical players in cell-to-cell communication, but their roles during development remain poorly understood. Nonetheless, disruption of extracellular pH and proton-sensing can affect cellular and protein functions, leading to developmental defects. Measuring extracellular protons has historically been hindered by technical constraints. Therefore, the authors developed a novel transgenic zebrafish line, Tg(ubi:pHluorin2-GPI), which ubiquitously expresses a ratiometric fluorescent pH sensor, tethered to the extracellular face of the plasma membrane using a glycosylphosphatidylinositol (GPI) anchor. Monitoring pHluorin2 fluorescence revealed dynamic and discrete domains of extracellular acidification, most notably in the extracellular space of the myotome, where the pH is very distinct to that within the T-tubules. Interestingly, knockdown of centronuclear myopathy genes Bin1b and MTM1 exhibit disruptions in T-tubule formation in association with perturbed myotome acidification. Therefore, this real-time reporter line can illuminate the role of extracellular pH during normal physiological development and in the pathogenesis of disease.

Ear Development. “The cochlea phenotypically differs from the vestibule in the Gfi1GFP/GFP mouse” by Zhuo Li, Hongzhi Chen, and Hao Feng.⁵ Anatomically, the inner ear is one of the most complex organs in the human body. It houses at least six sensory apparatuses, including the cochlea, two maculae (the utricle and saccule), and three ampullary cristae. These structures contain mechanosensory hair cells and non-sensory supporting cells, which may arise from a common progenitor, but subsequently co-ordinate with each other to maintain hearing and balance. Interestingly, Gfi1 knockout mice exhibit behavioral defects, including circling and desensitization to a startle response, both of which are consistent with inner ear anomalies, and recently, Gfi1 has been shown to regulate the maturation and maintenance of hair cells in the mammalian inner ear. In this study the authors used a different Gfi1GFP knockin mouse model to follow the fates of neonatal hair cells and supporting cells in the cochlea compared with the vestibule. Loss of Gfi1 results in reduced auditory hair cells, with the outer hair cells being more affected than the inner hair cells. However, vestibular hair cells remained unaffected. Interestingly, Gfi1 is never expressed in supporting cells, suggesting that Gfi1 plays a novel non-autonomous cell role that impacts cochlear supporting cell survival. Gfi1 therefore exhibits different functions in the cochlea and vestibule during inner ear development.