Developmental Dynamics最新文献

Background: During secondary palate formation, bilateral palatal shelves grow vertically to a horizontal position. This morphological change of the palatal shelves, defined as the palatal shelf elevation, occurs from embryonic day (E)-13.5 to E14 in mice. Palatal shelves show regional differences in elevation patterns along the anterior-posterior (AP) axis; however, the underlying mechanisms remain unclear. Material properties of the lingual/nasal and buccal/oral surfaces, especially stiffness, possibly contribute to different elevation patterns.

Results: Indentation test using atomic force microscopy was performed to measure the stiffness at the epithelial surface of the palatal shelf. Measurement of palatal shelf stiffness along the AP axis before and after elevation revealed that the lingual/nasal surface was softer than the buccal/oral surface in the posterior region before elevation and that the palatal shelf was stiffer after elevation than before elevation. Moreover, the thickness of epithelial cells on the lingual/nasal side was lower than that on the buccal/oral side before elevation.

Conclusion: Overall, our results suggest that epithelial cell thickness affects epithelial surface stiffness, causing regional differences in elevation patterns.

Background: Phosphatidylserine synthase (PSS), localized in the mitochondrial membrane, synthesizes phosphatidylserine. In humans, mutations in Pss lead to Lenz-Majewski hyperostotic dwarfism, a disorder affecting growth and development. The effects of Pss mutations on the growth of Drosophila melanogaster are not fully known. Hence, this study was conducted to investigate the effects of Pss knockdown on the growth and development of D. melanogaster.

Results: Enterocyte (EC)-specific Pss knockdown resulted in reduced cell size in the gut via reduced Akt signaling. EC-specific Pss knockdown was associated with a decrease in gut size, a change in gut pH, and reduced food intake. These abnormalities affected normal nutrient metabolism in larvae, leading to decreased secretion of Drosophila insulin-like peptides. Consequently, the reduced systemic Akt signaling at the organismal level resulted not only in impaired gut growth but also in abnormal organismal growth and development.

Conclusion: These findings highlight the significant role of the Pss gene in the growth and development of D. melanogaster.

Background: Mutations in cohesins cause cohesinopathies such as Cornelia de Lange Syndrome (CdLS) and Roberts Syndrome (RBS). Prior findings demonstrate that Esco2 (a cohesin activator) and Smc3 (a core cohesin subunit) regulate the CRL4 E3 ubiquitin ligase. SMC3 mutations, however, account for a small percentage of CdLS. Here, we test whether NIPBL, which when mutated is responsible for 65% of CdLS cases, also regulates CRL4.

Results: We report that Nipbl knockdown in zebrafish embryos produces developmental abnormalities and reduces the transcription of ddb1, which encodes a key component of CRL4 E3 ligase. The severity of phenotypes in Nipbl knockdown embryos is partially rescued by exogenous ddb1 mRNA, demonstrating that CRL4 ligase function is downstream of Nipbl. These findings suggest that aberrant accumulation of CRL4 ligase substrates contributes to developmental abnormalities. To test this model, we identified candidate CRL4 substrates in zebrafish embryos by LC-MS. The results reveal that elevated expression of one of these candidates, pparαa, is sufficient to produce developmental defects in zebrafish embryos.

Conclusions: Nipbl impacts CRL4 ligase activity via regulation of ddb1 expression. We provide evidence that the aberrant accumulation of substrates is sufficient to produce developmental abnormalities consistent with those observed in RBS and CdLS models.

Background: The endocannabinoid system is a neuromodulatory system implicated in cellular processes during both development and regeneration. The Mexican axolotl, one of only a few vertebrates capable of central nervous system regeneration, was used to examine the role of the endocannabinoid system in the regeneration of the tail and spinal cord following amputation.

Results: The endocannabinoid receptor CB1 was upregulated in the regenerating axolotl spinal cord by 4 hours following tail amputation, and this upregulation persisted for at least 14 days. The endocannabinoid receptor CB2 was upregulated later, between 7 and 14 days after tail amputation. Both CB1 and CB2 were located in ependymoglia and neurons within the regenerating spinal cord. Treatment with inverse agonists to inhibit CB1 (AM251) or CB2 (AM630) inhibited spinal cord and tail regeneration. During the first 7 days after injury, CB1 and CB2 expression was also necessary for the proliferation of ependymoglial cells and the regeneration of axons into the newly regenerated tail tissue. However, only CB1 was necessary for the differentiation of ependymoglia into immature neurons.

Conclusions: These studies are the first to examine the role of the endocannabinoid system during spinal cord regeneration in a regeneration-competent vertebrate.

Colorectal cancer (CRC) ranks among the leading causes of cancer-related morbidity and mortality worldwide. Despite progress in understanding its molecular intricacies, the management of CRC, especially in advanced stages, remains a significant clinical hurdle. This review delves into the evolving landscape of stem cell-based therapeutic strategies in CRC, with a specific focus on the interplay between cancer stem cells (CSCs) and CRC pathogenesis and treatment resistance. Highlighting the pivotal roles of CSCs in tumor initiation, progression, metastasis, and recurrence, the review comprehensively examines their involvement in CRC, ranging from normal colonic tissue to cancer initiation. The potential of stem cells for medicinal purposes in CRC management is explored, encompassing diverse modalities such as transplantation, differentiation therapy, immunotherapy, and gene/cell-based approaches. Challenges and opportunities associated with these strategies are also evaluated, providing insights into their clinical potential and limitations. The review also appraises preclinical investigations contributing to the understanding of CRC and stem cells. Current clinical trials, patient stratification strategies, and regulatory considerations related to stem cell-based therapies in CRC are scrutinized. Furthermore, the review explores emerging trends and future directions, including developments in stem cell technologies and ethical considerations. It highlights the transformative potential of stem cell-based therapeutic strategies in CRC.

Background: Bones develop to structurally balance strength and mobility. Bone developmental dynamics are influenced by whether an animal is ambulatory at birth. Precocial species, which are ambulatory at birth, develop advanced skeletal maturity in utero and experience postnatal development under mechanical loading. Here, we characterized postnatal bone development in the lower forelimbs of precocial goats using microcomputed tomography and histology. Our analysis focused on the two phalanges 1 (P1) bones and the partially fused metacarpal bone of the goat autopod from birth through adulthood.

Results: P1 cortical bone densified rapidly after birth, but cortical thickness increased continually through adulthood. Upon normalization by body mass, the P1 normalized polar moment of inertia was constant over time, suggestive of changes correlating with ambulatory loading. P1 trabecular bone increased in trabecular number and thickness until sexual maturity (12 months), while metacarpal trabeculae grew primarily through trabecular thickening. Unlike prenatal synostosis (i.e., bone fusion) of the metacarpal diaphysis, synostosis of the epiphyses occurred postnatally, prior to growth plate closure, through a unique fibrocartilaginous endochondral ossification.

Conclusions: These findings implicate ambulatory loading in postnatal bone development of precocial goats and identify a novel postnatal synostosis event in the caprine metacarpal epiphysis.

Background: CD163 is a scavenger receptor predominantly expressed on the surfaces of macrophages in various mammalian species and is a marker of anti-inflammatory (M2-like) macrophages. High density of CD163-positive tumor-associated macrophages (TAMs) is associated with worse prognosis in various patient tumors. Interestingly, studies on mice have shown that CD163-positive TAMs only infiltrate the margins of tumor tissues, not the center. Based on these observations, we hypothesized that circulating monocyte-derived macrophages (MDMs), which are the origin of most TAMs, do not express CD163 in mice.

Results: We examined CD163 expression in MDMs, differentiated from healthy animals in vitro, and in normal, pathogenic, and tumorigenic macrophages infiltrating various tumors and organs across multiple species including primates, rodents, cetartiodactylans, and carnivores. We found that MDMs, including TAMs, do not express CD163 in mice. Our findings also suggest that murine CD163-positive macrophages likely originate from a specific subset of resident macrophages, namely fetal liver monocytes/macrophages, as indicated by fetal analysis. Furthermore, we revealed that the CD163-negative expression pattern in MDMs is a trait shared by the rodent clade.

Conclusions: Rodent MDMs do not express CD163, a phenotype not shared with MDMs of other mammals. Our findings caution against the extrapolation of rodent experimental results to other animal models.