Current Topics in Developmental Biology最新文献

In mammals, differentiation of germ cells is crucial for sexual reproduction, involving complex signaling pathways and environmental cues defined by the somatic cells of the gonads. This review examines the long-standing model positing that all-trans retinoic acid (ATRA) acts as a meiosis-inducing substance (MIS) in the fetal ovary by inducing expression of STRA8 in female germ cells, while CYP26B1 serves as a meiosis-preventing substance (MPS) in the fetal testis by degrading ATRA and preventing STRA8 expression in the male germ cells until postnatal development. Recent genetic studies in the mouse challenge this paradigm, revealing that meiosis initiation in female germ cells can occur independently of ATRA signaling, with key roles played by other intrinsic factors like DAZL and DMRT1, and extrinsic signals such as BMPs and vitamin C. Thus, ATRA can no longer be considered as 'the' long-searched MIS. Furthermore, evidence indicates that CYP26B1 does not prevent meiosis by degrading ATRA in the fetal testis, but acts by degrading an unidentified MIS or synthesizing an equally unknown MPS. By emphasizing the necessity of genetic loss-of-function approaches to accurately delineate the roles of signaling molecules such ATRA in vivo, this chapter calls for a reevaluation of the mechanisms instructing and preventing meiosis initiation in the fetal ovary and testis, respectively. It highlights the need for further research into the molecular identities of the signals involved in these processes.

All-trans retinoic acid (ATRA) signaling is essential in numerous different biological contexts. This review highlights the diverse roles of ATRA during development, function, and diseases of the pancreas. ATRA is essential to specify pancreatic progenitors from gut tube endoderm, endocrine and exocrine differentiation, and adult islet function. ATRA concentration must be carefully regulated during the derivation of islet-like cells from human pluripotent stem cells (hPSCs) to optimize the expression of key pancreatic transcription factors while mitigating adverse and unwanted cell-types in these cultures. The ATRA pathway is integral to the pancreas and here we will present selected studies from decades of research that has laid the essential groundwork for ongoing projects dedicated to unraveling the complexities of ATRA signaling in the pancreas.

Retinoids, particularly all-trans-retinoic acid (ATRA), play crucial roles in various physiological processes, including development, immune response, and reproduction, by regulating gene transcription through nuclear receptors. This review explores the biosynthetic pathways, homeostatic mechanisms, and the significance of retinoid-binding proteins in maintaining ATRA levels. It highlights the intricate balance required for ATRA homeostasis, emphasizing that both excess and deficiency can lead to severe developmental and health consequences. Furthermore, the associations are discussed between ATRA dysregulation and several diseases, including various genetic disorders, cancer, endometriosis, and heart failure, underscoring the role of retinoid-binding proteins like RBP1 in these conditions. The potential for gene-environment interactions in retinoid metabolism is also examined, suggesting that dietary factors may exacerbate genetic predispositions to ATRA-related pathologies. Methodological advancements in quantifying ATRA and its metabolites are reviewed, alongside the challenges inherent in studying retinoid dynamics. Future research directions are proposed to further elucidate the role of ATRA in health and disease, with the aim of identifying therapeutic targets for conditions linked to retinoid signaling dysregulation.

Alterations in tissue expression levels of both retinol-binding protein 2 (RBP2) and retinol-binding protein 4 (RBP4) have been associated with metabolic disease, specifically with obesity, glucose intolerance and hepatic steatosis. Our laboratories have shown that this involves novel pathways not previously considered as possible linkages between impaired retinoid metabolism and metabolic disease development. We have established both biochemically and structurally that RBP2 binds with very high affinity to very long-chain unsaturated 2-monoacylglycerols like the canonical endocannabinoid 2-arachidonoyl glycerol (2-AG) and other endocannabinoid-like substances. Binding of retinol or 2-MAGs involves the same binding pocket and 2-MAGs are able to displace retinol binding. Consequently, RBP2 is a physiologically relevant binding protein for endocannabinoids and endocannabinoid-like substances and is a nexus where the very potent retinoid and endocannabinoid signaling pathways converge. When Rbp2-null mice are challenged orally with fat, this gives rise to elevated levels in the proximal small intestine of both 2-AG and the incretin hormone glucose-dependent insulinotropic polypeptide (GIP) in the proximal small intestine. We propose that elevation of GIP concentrations upon high fat diet feeding gives rise to obesity and the other elements of metabolic disease seen in Rbp2-null mice. Unexpectedly, we observed that RBP4 is present in secretory granules of the GIP-secreting intestinal K-cells and is co-secreted with GIP in response to a stimulus that provokes GIP secretion. Moreover, RBP4 is co-secreted along with glucagon from pancreatic alpha-cells in response to a secretory stimulus. The association during the secretory process of RBP4 with potent hormones that regulate metabolism (GIP and glucagon) accounts for at least some of the metabolic disease seen upon overexpression of Rbp4.

Retinoic acid (RA) signaling plays multiple essential roles in development of the head and face. Animal models with mutations in genes involved in RA signaling have enabled understanding of craniofacial morphogenic processes that are regulated by the retinoid pathway. During craniofacial morphogenesis RA signaling is active in spatially restricted domains defined by the expression of genes involved in RA production and RA breakdown. The spatial distribution of RA signaling changes with progressive development, corresponding to a multiplicity of craniofacial developmental processes that are regulated by RA. One important role of RA signaling occurs in the hindbrain. There RA contributes to specification of the anterior-posterior (AP) axis of the developing CNS and to the neural crest cells (NCC) which form the bones and nerves of the face and pharyngeal region. In the optic vesicles and frontonasal process RA orchestrates development of the midface, eyes, and nasal airway. Additional roles for RA in craniofacial development include regulation of submandibular salivary gland development and maintaining patency in the sutures of the cranial vault.

All-trans retinoic acid (ATRA) signaling is a major pathway regulating numerous differentiation, proliferation, and patterning processes throughout life. ATRA biosynthesis depends on the nutritional availability of vitamin A and other retinoids and carotenoids, while it is sensitive to dietary and environmental toxicants. This nutritional and environmental influence requires a robustness response that constantly fine-tunes the ATRA metabolism to maintain a context-specific, physiological range of signaling levels. The ATRA metabolic and signaling network is characterized by the existence of multiple enzymes, transcription factors, and binding proteins capable of performing the same activity. The partial spatiotemporal expression overlap of these enzymes and proteins yields different network compositions in the cells and tissues where this pathway is active. Genetic polymorphisms affecting the activity of individual network components further impact the network composition variability and the self-regulatory feedback response to ATRA fluctuations. Experiments directly challenging the robustness response uncovered a Pareto optimality in the ATRA network, such that some genetic backgrounds efficiently deal with excess ATRA but are very limited in their robustness response to reduced ATRA and vice versa. We discuss a network-focused framework to describe the robustness response and the Pareto optimality of the ATRA metabolic and signaling network.

For mammalian spermatogenesis to proceed normally, it is essential that the population of testicular progenitor cells, A undifferentiated spermatogonia (A_undiff), undergoes differentiation during the A to A1 transition that occurs at the onset of spermatogenesis. The commitment of the A_undiff population to differentiation and leaving a quiescent, stem-like state gives rise to all the spermatozoa produced across the lifespan of an individual, and ultimately determines male fertility. The action of all-trans retinoic acid (atRA) on the A_undiff population is the determining factor that induces this change. Sertoli cells, omnipresent, nurse cells within the mammalian testis are responsible for synthesizing the atRA that prompts this change in the neonatal testicular environment. The mechanism of atRA synthesis and signaling has been robustly explored and, in this review, we have summarized what is currently known about the action of testicular atRA at the onset of spermatogenesis. We have combined this with evidence gained from prominent genetic studies that have further elucidated the function of genes critical to atRA synthesis. We have additionally described the effects of the first pulse of atRA delivered to the germ cells of the testis, which has been investigated using WIN 18,446 treatment which prevents atRA synthesis and induces spermatogenic synchrony. This method provides unparalleled resolution into cell and stage specific testicular changes, and combined with transgenic animal models, has allowed researchers to elucidate much regarding the onset of spermatogenesis.

Vitamin A (all-trans-retinol; at-Rol) and its derivatives, known as retinoids, have been adopted by vertebrates to serve as visual chromophores and signaling molecules, particularly in the eye/retina. Few tissues rely on retinoids as heavily as the retina, and the study of genetically modified mouse models with deficiencies in specific retinoid-metabolizing proteins has allowed us to gain insight into the unique or redundant roles of these proteins in at-Rol uptake and storage, or their downstream roles in retinal development and function. These processes occur during embryogenesis and continue throughout life. This review delves into the role of these genes in supporting retinal function and maps the impact that genetically modified mouse models have had in studying retinoid-related genes. These models display distinct perturbations in retinoid biochemistry, physiology, and metabolic flux, mirroring human ocular diseases.

All-trans RA (ATRA) is a small molecule derived from retinol (vitamin A) that directly controls gene expression at the transcriptional level by serving as a ligand for nuclear ATRA receptors. ATRA is produced by ATRA-generating enzymes that convert retinol to retinaldehyde (retinol dehydrogenase; RDH10) followed by conversion of retinaldehyde to ATRA (retinaldehyde dehydrogenase; ALDH1A1, ALDH1A2, or ALDH1A3). Determining what ATRA normally does during vertebrate development has been challenging as studies employing ATRA gain-of-function (RA treatment) often do not agree with genetic loss-of-function studies that remove ATRA via knockouts of ATRA-generating enzymes. In mouse embryos, ATRA is first generated at stage E7.5 by ATRA-generating enzymes whose genes are first expressed at that stage. This article focuses upon what ATRA normally does at early stages based upon these knockout studies. It has been observed that early-generated ATRA performs three essential functions: (1) activation of genes that control hindbrain and spinal cord patterning; (2) repression of Fgf8 in the heart field and caudal progenitors to provide an FGF8-free region in the trunk essential for somitogenesis, heart morphogenesis, and initiation of forelimb fields; and (3) actions that stimulate invagination of the optic vesicle to form the optic cup.

Animals perceiving light through visual pigments have evolved pathways for absorbing, transporting, and metabolizing the precursors essential for synthesis of their retinylidene chromophores. Over the past decades, our understanding of this metabolism has grown significantly. Through genetic manipulation, researchers gained insights into the metabolic complexity of the pathways mediating the flow of chromophore precursors throughout the body, and their enrichment within the eyes. This exploration has identified transport proteins and metabolizing enzymes for these essential lipids and has revealed some of the fundamental regulatory mechanisms governing this process. What emerges is a complex framework at play that maintains ocular retinoid homeostasis and functions. This review summarizes the recent advancements and highlights future research directions that may deepen our understanding of this complex metabolism.