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Retinoids and the retinoic acid (RA) signaling pathway. The chemical structures of all-trans retinol, all-trans retinal and all-trans retinoic acid are indicated. In vertebrates, retinol, bound to retinol binding protein (RBP) and transthyretin (TTR), travels in the blood stream and enters target cells through the transmembrane receptor STRA6. Cellular retinol binding proteins (CRBPs) stabilize retinol within the cell. The reversible oxidation of retinol into retinal is catalyzed by cytosolic alcohol dehydrogenases (ADHs/RolDHs) or membrane-bound short-chain dehydrogenases/reductases (SDRs). Subsequently, retinal is irreversibly converted into RA by enzymes of the aldehyde dehydrogenase family (ALDHs). The signaling molecule RA is either degraded by proteins of the cytochrome P450 family, chiefly CYP26, which oxidize RA to various inactive metabolites, or it is transported into the nucleus by cellular retinoic acid binding proteins (CRABPs). Within the nucleus, RA binds to a heterodimer of retinoic acid receptor (RAR) and retinoid X receptor (RXR). The RAR/RXR heterodimer is bound to retinoic acid response elements (RAREs) in the regulatory region of RA target genes and fixation of the ligand, RA, causes a conformational change inducing the release of co-repressors and the recruitment of co-activator complexes, thus leading to the initiation of gene transcription. As a diffusible morphogen, RA can act both within the cell where it is produced and at a distance, for example on neighboring cells.
Source publication
Retinoic acid (RA) is an important signaling molecule mediating intercellular communication through vertebrate development. Here, we present and discuss recent information on the roles of the RA signaling pathway in spinal cord development. RA is an important player in the patterning and definition of the spinal cord territory from very early stage...
Citations
... RA, the most important metabolite of vitamin A, performs the vast majority of vitamin A metabolic functions. After entering the nucleus, RA regulates the expression of target genes by binding to RA receptors [13]. Studies have shown that RA promotes myogenesis in zebrafish [14] and Angus cattle [15], while inhibit differentiation of chick embryo limb myoblasts [16]. ...
Background
Vitamin A and retinoic acid (RA, a metabolite of vitamin A), are inextricably involved to the development of skeletal muscle in animals. However, the mechanisms regulating skeletal muscle development by vitamin A remain poorly reported. The current study designed to investigate the underlying mechanism of vitamin A affecting myogenic differentiation of lamb myoblasts through transcriptome sequencing (RNA-Seq) and gene function validation experiments. It provides a theoretical basis for elucidating the regulation of vitamin A on skeletal muscle development as well as for improving the economic benefits of the mutton sheep industry.
Results
Newborn lambs were injected with 7,500 IU vitamin A, and longissimus dorsi (LD) muscle tissue was surgically sampled for RNA-Seq analysis and primary myoblasts isolation at 3 weeks of age. The results showed that a total of 14 down-regulated and 3 up-regulated genes, were identified between control and vitamin A groups. Among them, BHLHE40 expression was upregulated in vitamin A group lambs. Furthermore, BHLHE40 expression is significantly increased after initiation of differentiation in myoblasts, and RA addition during differentiation greatly promoted BHLHE40 mRNA expression. In vitro, RA inhibited myoblasts proliferation and promoted myoblasts myogenic differentiation through BHLHE40. Moreover, BHLHE40 was proved to inhibit the expression of the DNA binding inhibitor 3 (ID3), and meanwhile, ID3 could effectively promote myoblasts proliferation and inhibit myoblasts myogenic differentiation.
Conclusions
Taken together, our results suggested that vitamin A inhibited myoblasts proliferation and promoted myoblasts myogenic differentiation by inhibiting ID3 expression through BHLHE40.
... Retinoic acid in vivo is produced by retinol in the sequential action of retinol dehydrogenase and retinaldehyde dehydrogenase. Subsequently, retinoic acid binds to heterodimer of the retinoic acid receptor (RAR) and retinoic acid X receptor (RXR), and the complex binds to retinoic acid response elements (RAREs) in the regulatory regions of RA target genes, ultimately causing the transcription of the genes to be affected [61]. Consistent with the in vivo results, RA improved mitochondrial biogenesis and function, promoted the production of oxidative muscle fibers in sheep primary myoblasts. ...
Background:
Vitamin A (VA) and its metabolite, retinoic acid (RA), are of great interest for their wide range of physiological functions. However, the regulatory contribution of VA to mitochondrial and muscle fiber composition in sheep has not been reported.
Method:
Lambs were injected with 0 (control) or 7,500 IU VA palmitate into the biceps femoris muscle on d 2 after birth. At the age of 3 and 32 weeks, longissimus dorsi (LD) muscle samples were obtained to explore the effect of VA on myofiber type composition. In vitro, we investigated the effects of RA on myofiber type composition and intrinsic mechanisms.
Results:
The proportion of type I myofiber was greatly increased in VA-treated sheep in LD muscle at harvest. VA greatly promoted mitochondrial biogenesis and function in LD muscle of sheep. Further exploration revealed that VA elevated PGC-1α mRNA and protein contents, and enhanced the level of p38 MAPK phosphorylation in LD muscle of sheep. In addition, the number of type I myofibers with RA treatment was significantly increased, and type IIx myofibers was significantly decreased in primary myoblasts. Consistent with in vivo experiment, RA significantly improved mitochondrial biogenesis and function in primary myoblasts of sheep. We then used si-PGC-1α to inhibit PGC-1α expression and found that si-PGC-1α significantly abrogated RA-induced the formation of type I myofibers, mitochondrial biogenesis, MitoTracker staining intensity, UQCRC1 and ATP5A1 expression, SDH activity, and enhanced the level of type IIx muscle fibers. These data suggested that RA improved mitochondrial biogenesis and function by promoting PGC-1α expression, and increased type I myofibers. In order to prove that the effect of RA on the level of PGC-1α is caused by p38 MAPK signaling, we inhibited the p38 MAPK signaling using a p38 MAPK inhibitor, which significantly reduced RA-induced PGC-1α and MyHC I levels.
Conclusion:
VA promoted PGC-1α expression through the p38 MAPK signaling pathway, improved mitochondrial biogenesis, and altered the composition of muscle fiber type.
... When VA enters the cell, it produces RA under the action of dehydrogenase. In the nucleus, RA binds to the heterodimer of retinoic acid receptor (RAR) and retinoid X receptor (RXR) to perform its biological function (14). ...
Introduction
Vitamin A (VA) and its metabolite, retinoic acid (RA) possess several biological functions. This report investigated whether neonatal intramuscular VA injection affected antioxidative activity and meat quality in longissimus dorsi (LD) muscle of lambs.
Methods
Lambs were injected with 0 (control) or 7,500 IU VA palmitate into the biceps femoris muscle on day 2 after birth. At 3, 12, and 32 weeks of age, blood samples were collected in the jugular vein for serum levels of RA and muscle samples were collected in the biceps femoris for analysis of relative mRNA expression of enzyme contributors to retinoid metabolism. All animals were harvested at 32 weeks of age and muscle samples were collected to explore the role of VA on the meat quality and antioxidant capacity of lambs.
Results and discussion
Our results indicated that VA increased the redness, crude protein, and crude fat (p < 0.05), without affecting moisture, ash, and amino acid composition in LD muscle (p > 0.05). In addition, VA increased catalase (CAT) activity and decreased malondialdehyde (MDA) levels in LD muscle (p < 0.05). Meanwhile, greater levels of CAT and NRF2 mRNA and protein contents with VA treatment were observed in LD muscle (p < 0.05), partly explained by the increased level of RA (p < 0.05). Collectively, our findings indicated that VA injection at birth could improve lamb meat quality by elevating the redness, crude protein, crude fat, and antioxidative capacity in LD muscle of lambs.
... One essential part of the process included the induced growth and spinal motor differentiation of embryoid bodies, which were generated from mouse embryonic stem cells (39). Prior research has indicated the role of retinoic acid signaling in the development and neuronal differentiation of the spinal cord (40). The culturing of mouse embryoid bodies with 0.01 M retinoic acid allowed for the induction of the cell specifications toward spinal motor neuron identities. ...
Ketamine is a dissociative anesthetic and antidepressant with several biological targets. Among the many targets, ketamine, notably, has an antagonistic effect on molecular N-methyl-D-aspartate (NMDA) receptors and has been identified as a non-competitive inhibitor of these receptors. Although ketamine has a wide range of therapeutic uses in the clinical setting, it is often used recreationally due to its psychoactive and analgesic effects. Regardless of the indication, prenatal exposure to ketamine has been widely investigated. The misuse of this drug, particularly in pregnant women, has been a point of concern. The neurotoxic potential of ketamine positions it as a danger to a developing fetus. Furthermore, the ability of ketamine to cross the blood-placental barrier poses a threat to the health and maturation processes of the neonate. This paper reviewed published work that explores the mechanisms through which prenatal ketamine exposure can cause altered neurodevelopment, neurobehavior, and the physiological consequences that follow. By exploring investigations using multiple different subjects such as: rodents, non-human primates, and human subjects, this paper develops a full picture of the existing data to generate a strong foundation for improved and informed public health policies.
... A recent RNA-seq analysis revealed transcriptional heterogeneity between premigratory NC and definitive RP cells, uncovering a set of genes expressed specifically at the onset of the RP stage (Ofek et al., 2021). One of these genes is Raldh2/Aldh1a2, that encodes an enzyme responsible for the biosynthesis of the morphogen retinoic acid (RA) (Haselbeck et al., 1999), central to multiple neurodevelopmental processes (Diez del Corral and Morales, 2014;Lara-Ramírez et al., 2013;Wilson et al., 2004). RA derived from the Raldh2-expressing somitic mesoderm has been described as a key factor in NT development, including control of motoneuron specification (Novitch et al., 2003;Wilson et al., 2004) and initiation but not maintenance of NC EMT and emigration (Martínez-Morales et al., 2011). ...
Production and emigration of neural crest cells is a transient process followed by the emergence of the definitive roof plate. The mechanisms regulating the end of neural crest ontogeny are poorly understood. Whereas early crest development is stimulated by mesoderm-derived retinoic acid, we report that the end of the neural crest period is regulated by retinoic acid synthesized in the dorsal neural tube. Inhibition of retinoic acid signaling in the neural tube prevents the normal upregulation of BMP inhibitors in the nascent roof plate and prolongs the period of BMP responsiveness which otherwise ceases close to roof plate establishment. Consequently, neural crest production and emigration are extended well into the roof plate stage. In turn, extending the activity of neural crest-specific genes inhibits the onset of retinoic acid synthesis in roof plate suggesting a mutual repressive interaction between neural crest and roof plate traits. Although several roof plate-specific genes are normally expressed in the absence of retinoic acid signaling, roof plate and crest markers are co-expressed in single cells and this domain also contains dorsal interneurons. Hence, the cellular and molecular architecture of the roof plate is compromised. Collectively, our results demonstrate that neural tube-derived retinoic acid, via inhibition of BMP signaling, is an essential factor responsible for the end of neural crest generation and the proper segregation of dorsal neural lineages.
... Tightly controlled gradients of RA and its receptor (RAR) ensure spatiotemporal coordination of these intricate cellular events. Subtypes of RAR have distinct expression profiles in open versus closed neural tubes, with RARγ heavily expressed in the former and RARβ in the latter 114,115 . If these processes go awry, anterior or posterior regions of the neural tube fail to close -causing anencephaly and spina bifida, respectively, which are two of the most common congenital defects 95 . ...
Mammalian development demands precision. Millions of molecules must be properly
located in temporal order, and their function regulated, to orchestrate important steps in
cell cycle progression, apoptosis, migration and differentiation, to shape developing embryos.
Ubiquitin and its associated enzymes act as cellular guardians to ensure precise spatio-temporal
control of key molecules during each of these important cellular processes. Loss of precision
results in numerous examples of embryological disorders or even cancer. This Review discusses the crucial roles of E3 ubiquitin ligases during key steps of early mammalian development and their roles in human disease, and considers how new methods to manipulate and exploit the ubiquitin regulatory machinery — for example, the development of molecular glues and PROTACs — might facilitate clinical therapy.
... Tightly controlled gradients of RA and its receptor (RAR) ensure spatiotemporal coordination of these intricate cellular events. Subtypes of RAR have distinct expression profiles in open versus closed neural tubes, with RARγ heavily expressed in the former and RARβ in the latter 114,115 . If these processes go awry, anterior or posterior regions of the neural tube fail to close -causing anencephaly and spina bifida, respectively, which are two of the most common congenital defects 95 . ...
Mammalian development demands precision. Millions of molecules must be properly located in temporal order, and their function regulated, to orchestrate important steps in cell cycle progression, apoptosis, migration and differentiation, to shape developing embryos. Ubiquitin and its associated enzymes act as cellular guardians to ensure precise spatio-temporal control of key molecules during each of these important cellular processes. Loss of precision results in numerous examples of embryological disorders or even cancer. This Review discusses the crucial roles of E3 ubiquitin ligases during key steps of early mammalian development and their roles in human disease, and considers how new methods to manipulate and exploit the ubiquitin regulatory machinery - for example, the development of molecular glues and PROTACs - might facilitate clinical therapy.
... The cells were differentiated to NPCs and transitioned towards an OL fate following a published protocol with some modifications (Douvaras and Fossati, 2015) ( Figure 1A). PAX6, a classical marker for NPCs, was used to confirm the presence of NPCs at culture day 8 programmed either with Wnt-C59 (a Wnt pathway inhibitor, a driver of rostral CNS fate (Hermanto et al., 2019;Patapoutian and Reichardt, 2000)) or Retinoic Acid (RA, a driver of caudal CNS fate (Goldman and Kuypers, 2015;Lara-Ramírez et al., 2013)) ( Figure 1F,G,H). ...
The intellectual disability found in people with Down syndrome (DS) is associated with a decrease in white matter in the central nervous system. To study the mechanism of this myelination deficit, we differentiated two isogenic lines of induced pluripotent stem cells (iPSCs) derived from people with DS into brain-like and spinal cord-like neural progenitor cells (NPCs) and promoted a transition towards oligodendroglial fate by activating the Sonic hedgehog (SHH) pathway. In the spinal cord-like trisomic cells, we found no difference in expression of OLIG2 or NKX2.2, two transcription factors essential for commitment to the oligodendrocyte (OL) lineage. However, in the brain-like trisomic NPCs, OLIG2 is significantly upregulated and is associated with reduced expression of NKX2.2. We found that this gene dysregulation and block in NPC transition can be normalized by increasing the concentration of a SHH pathway agonist (SAG) during differentiation. These results underscore the importance of regional and cell type differences in gene expression in DS and demonstrate that modulation of SHH signaling in trisomic cells can rescue an early perturbed step in neural lineage specification in DS.
... This study revealed that the recruitment of co-activators to the RAR/RXR heterodimers occurs at specific RAREs sites. The binding of the RAR/RXR heterodimer to RAREs, and recruitment of coactivators, leads to the transcription of retinoid target genes, for further detail please see [30,31] (Figure 2). ...
Retinoic acid (RA) agents possess anti-tumor activity through their ability to induce cellular differentiation. However, retinoids have not yet been translated into effective systemic treatments for most solid tumors. RA signaling is mediated by the following two nuclear retinoic receptor subtypes: the retinoic acid receptor (RAR) and the retinoic X receptor (RXR), and their isoforms. The identification of mutations in retinoid receptors and other RA signaling pathway genes in human cancers offers opportunities for target discovery, drug design, and personalized medicine for distinct molecular retinoid subtypes. For example, chromosomal translocation involving RARA occurs in acute promyelocytic leukemia (APL), and all-trans retinoic acid (ATRA) is a highly effective and even curative therapeutic for APL patients. Thus, retinoid-based target discovery presents an important line of attack toward designing new, more effective strategies for treating other cancer types. Here, we review retinoid signaling, provide an update on retinoid agents and the current clinical research on retinoids in cancer, and discuss how the retinoid pathway genotype affects the ability of retinoid agents to inhibit the growth of colorectal cancer (CRC) cells. We also deliberate on why retinoid agents have not shown clinical efficacy against solid tumors and discuss alternative strategies that could overcome the lack of efficacy.
... Taken together, these data suggest that RA both establishes/maintains a broad dP identity and initiates the dI4-dI6 fate specification program. However, it has been challenging to unravel the specific functions of RA, given its multiple roles during the spinal cord development (Lara-Ramírez et al., 2013). Newly developed stem cell models will be invaluable for dissecting the transcriptomic mechanisms by which RA regulates the dI4-dI6 identities in the intermediate spinal cord (Gupta et al., 2018). ...
The spinal cord is functionally and anatomically divided into ventrally derived motor circuits and dorsally derived somatosensory circuits. Sensory stimuli originating either at the periphery of the body, or internally, are relayed to the dorsal spinal cord where they are processed by distinct classes of sensory dorsal interneurons (dIs). dIs convey sensory information, such as pain, heat or itch, either to the brain, and/or to the motor circuits to initiate the appropriate response. They also regulate the intensity of sensory information and are the major target for the opioid analgesics. While the developmental mechanisms directing ventral and dorsal cell fates have been hypothesized to be similar, more recent research has suggested that dI fates are specified by novel mechanisms. In this review, we will discuss the molecular events that specify dorsal neuronal patterning in the spinal cord, thereby generating diverse dI identities. We will then discuss how this molecular understanding has led to the development of robust stem cell methods to derive multiple spinal cell types, including the dIs, and the implication of these studies for treating spinal cord injuries and neurodegenerative diseases.
This article is categorized under:
• Neurological Diseases > Neurological Diseases > Stem Cells and Development
Abstract
Developmentally guided strategies to generate different populations of stem‐cell derived spinal sensory interneurons
