Retinoic acid (RA) is a metabolite of vitamin A (retinol) that plays various roles in development to influence differentiation, patterning, and organogenesis. RA also serves as a crucial homeostatic regulator in adult tissues. The role of RA and its associated pathways are well conserved from zebrafish to humans in both development and disease. This makes the zebrafish a natural model for further interrogation into the functions of RA and RA-associated maladies for the sake of basic research, as well as human health. In this review, we explore both foundational and recent studies using zebrafish as a translational model for investigating RA from the molecular to the organismal scale.

Introduction: Acute kidney injury (AKI) is a complex clinical condition characterized by decline in renal function and widespread transcriptional dysregulation. While transcriptomic studies that compare human and other mammalian models of AKI have provided insight, much less is known about commonalities and contrasts between mammalian models and nontraditional and regenerative laboratory models. Understanding these molecular level responses to injury in both regenerative and non-regenerative models may reveal conserved and unique pathways in renal repair.Methods: To investigate transcriptional responses to AKI across species, we incorporated newly available RNA-seq data from zebrafish, axolotl, and spiny mouse models into an expanded cross-species comparative analysis. These were analyzed alongside existing and previously analyzed data from both human and mouse (Mus) models. Differential gene expression and gene-ontology (GO) enrichment analyses we utilized to identify conserved and regeneration-specific during injury and recovery phases.Results: Comparative transcriptomic analysis revealed distinct transcriptional programs in each species during AKI, including both shared and species-specific responses. Of note, zebrafish show differential expression of apolipoproteins, molecules of increasing interest to the greater field of nephrology. In the recovery setting, we show that animals with regenerative capacity have conserved and divergent transcriptional programs.Discussion: Our findings demonstrate that non-traditional animal models of AKI, such as zebrafish, axolotls, and spiny mice, provide valuable insights into the molecular basis of kidney regeneration. The identification of conserved and divergent injury responses suggests evolutionary conservation in core AKI mechanisms, while also pointing to regeneration-associated transcriptional programs that could inform future therapeutic strategies. This work underscores the importance of using non-traditional models as well as the value in comparative analysis with traditional models and clinical data.

Endocannabinoid signaling plays a significant role in neurogenesis and nervous system physiology, but its roles in the development of other tissues are just beginning to be appreciated. Previous reports have shown the presence of the key endocannabinoid receptor Cannabinoid receptor 1 (CB1 or Cnr1) in multiciliated (MCC) tissues and its upregulation in kidney diseases, yet the relationship between Cnr1 and renal MCC development is unknown. Here, we report that Cnr1 is essential for cilia development across tissues and regulates renal MCCs via cyclic AMP (cAMP) signaling during zebrafish embryogenesis. Using a combination of genetic and pharmacological studies, we found that the loss of function, agonism and antagonism of cnr1 all lead to reduced mature renal MCC populations. cnr1 deficiency also led to reduced cilia development across tissues, including the pronephros, ear, Kupffer’s vesicle (KV), and nasal placode. Interestingly, treatment with the cAMP activator Forskolin (FSK) restored renal MCC defects in agonist-treated embryos, suggesting that cnr1 mediates cAMP signaling in renal MCC development. Meanwhile, treatment with the cAMP inhibitor SQ-22536 alone or with cnr1 deficiency led to reduced MCC populations, suggesting that cnr1 also mediates renal MCC development independently of cAMP signaling. Our findings indicate that cnr1 has a critical role in controlling renal MCC development both via cAMP signaling and an independent pathway, further revealing implications for ciliopathies and renal diseases.

Introduction: The developing zebrafish nephron contains a diverse repertoire of cell populations with intrinsically dynamic roles and interactions. Previous studies characterizing these populations have utilized genetic approaches based on powerful molecular methods, such as in situ hybridization, immunohistochemistry, and both live and fixed imaging. However, our understanding of the cellular characteristics of the populations necessary for renal development in the zebrafish model is lacking in comparison to our understanding of the genetic/ morphogenic drivers of nephron segmentation. Methods: To investigate the potential drivers of nephron development from the population perspective, we incorporated traditional molecular tools for determining cellular characteristics as well as algorithmic based optimization methods. We synthesized multiple ODE based models to investigate hypotheses surrounding populations existing in early zebrafish nephron development. Results: Our model based findings showed that deferential forms of fate processes may be necessary for zebrafish pronephros development. Also, we provide evidence for differentiated populations being the potential drivers of renal development rather than progenitor populations. Discussion: Our findings further bring forward the idea that differentiated populations are vital for the growth and development at the single nephron level in the zebrafish model. We also continue the investigation of varied forms of fate being necessary in renal development.