Role Of Retinoic Acid Signaling Research Articles

Editorial: The role of retinoic acid signaling in maintenance and regeneration of the CNS: from mechanisms to therapeutic targeting

Editorial: The role of retinoic acid signaling in maintenance and regeneration of the CNS: from mechanisms to therapeutic targeting

Pulse Activation of Retinoic Acid Receptor Enhances Hematopoietic Stem Cell Homing by Controlling CXCR4 Membrane Presentation.

The interplay between metabolic signaling and stem cell biology has gained increasing attention, though the underlying molecular mechanisms remain incompletely elucidated. In this study, we identify and characterize the role of adapalene (ADA), a retinoic acid receptor (RAR) agonist, in modulating the migration behavior of hematopoietic stem cells (HSCs). Our initial findings reveal that ADA treatment suppresses hematopoietic stem and progenitor cell (HSPC) mobilization induced by AMD3100 and G-CSF. Furthermore, we demonstrate that ADA treatment upregulates the surface expression of CXCR4 on HSPCs, resulting in enhanced chemotaxis towards CXCL12. Mechanistically, our study suggests that ADA enhances CXCR4 surface presentation without increasing CXCR4 mRNA levels, pointing towards a non-canonical role of RAR signaling in regulating intracellular trafficking of CXCR4. In vivo experiments show that ADA administration significantly enhances HSC homing efficiency. Additionally, competitive transplantation assays indicate a marked increase in donor chimerism following ADA treatment. These findings highlight the critical role of retinoic acid signaling in regulating HSC homing and suggest its potential for advancing novel HSC-based therapeutic strategies.

Understanding and modeling regional specification of the human ganglionic eminence.

Inhibitory neurons originating from the ventral forebrain are associated with several neurological conditions. Distinct ventral forebrain subpopulations are generated from topographically defined zones; lateral-, medial- and caudal ganglionic eminences (LGE, MGE and CGE), yet key specification factors often span across developing zones contributing to difficulty in defining unique LGE, MGE or CGE profiles. Here we use human pluripotent stem cell (hPSC) reporter lines (NKX2.1-GFP and MEIS2-mCherry) and manipulation of morphogen gradients to gain greater insight into regional specification of these distinct zones. We identified Sonic hedgehog (SHH)-WNT crosstalk in regulating LGE and MGE fate and uncovered a role for retinoic acid signaling in CGE development. Unraveling the influence of these signaling pathways permitted development of fully defined protocols that favored generation of the three GE domains. These findings provide insight into the context-dependent role of morphogens in human GE specification and are of value for invitro disease modeling and advancement of new therapies.

Reconstituting human somitogenesis in vitro.

The segmented body plan of vertebrates is established during somitogenesis, a well-studied process in model organisms; however, the details of this process in humans remain largely unknown owing to ethical and technical limitations. Despite recent advances with pluripotent stem cell-based approaches1-5, models that robustly recapitulate human somitogenesis in both space and time remain scarce. Here we introduce a pluripotent stem cell-derived mesoderm-based 3D model of human segmentation and somitogenesis-which we termed 'axioloid'-that captures accurately the oscillatory dynamics of the segmentation clock and the morphological and molecular characteristics of sequential somite formation in vitro. Axioloids show proper rostrocaudal patterning of forming segments and robust anterior-posterior FGF-WNT signalling gradients and retinoic acid signalling components. We identify an unexpected critical role of retinoic acid signalling in the stabilization of forming segments, indicating distinct, but also synergistic effects of retinoic acid and extracellular matrix on the formation and epithelialization of somites. Comparative analysis demonstrates marked similarities of axioloids to the human embryo, further validated by the presence of a Hox code in axioloids. Finally, we demonstrate the utility of axioloids for studying the pathogenesis of human congenital spine diseases using induced pluripotent stem cells withmutations in HES7 and MESP2. Our results indicate that axioloids represent a promising platform for the study of axial development and disease in humans.

Retinoic acid signaling in mouse retina endothelial cells is required for early angiogenic growth

The development of the retinal vasculature is essential to maintain health of the tissue, but the developmental mechanisms are not completely understood. The aim of this study was to investigate the cell-autonomous role of retinoic acid signaling in endothelial cells during retina vascular development. Using a temporal and cell-specific mouse model to disrupt retinoic acid signaling in endothelial cells in the postnatal retina (Pdgfbicre/+dnRAR403fl/fl mutants), we discovered that angiogenesis in the retina is significantly decreased with a reduction in retina vascularization, endothelial tip cell number and filipodia, and endothelial ‘crowding’ of stalk cells. Interestingly, by P15, the vasculature can overcome the early angiogenic defect and fully vascularized the retina. At P60, the vasculature is intact with no evidence of retina cell death or altered blood retinal barrier integrity. Further, we identified that the angiogenic defect seen in mutants at P6 correlates with decreased Vegfr3 expression in endothelial cells. Collectively, our work identified a previously unappreciated function for endothelial retinoic acid signaling in early retinal angiogenesis.

Machinery and Developmental Role of Retinoic Acid Signaling in Echinoderms.

Although a recent genomic survey revealed its ancient evolutionary origin in the animal kingdom, retinoic acid (RA) signaling was previously thought to be unique to chordates. Echinoderms are of critical interest in researching the evolutionary history of RA signaling, as they represent a basal group of deuterostomes. Furthermore, our previous works have suggested that echinoderms may possess the ancestral function of RA signaling for metamorphosis regulation. In this paper, to facilitate future studies of RA signaling in echinoderms, we provide an overview of RA machinery in echinoderms, identify its signaling components, and discuss its developmental role.

P039 The role of α4β7+CLA+ ‘dual tropic’ T cells in inflammatory bowel disease

Abstract Background Upon activation, T cells upregulate cell-surface molecules that enable entry into peripheral tissues. Retinoic acid (RA) produced by gut DC induces integrin α4β7 required for gut homing and represses CLA which facilitates skin entry; hence, these markers are usually reciprocally expressed. We aimed to identify the mechanisms enabling dual tropism, define the properties of α4β7+CLA+ T cells and compare blood and intestinal α4β7+CLA+ T cells in health and IBD. Methods Using flow cytometry, expression of α4β7 and CLA was assessed on (i) ex vivo human T cells from blood and intestinal tissue and; (ii) naïve CD4 T cells stimulated in vitro with antibodies (anti-CD3/28/2), or allogeneic DCs. The role of RA signalling and p38MAPK in CLA expression were investigated with respective antagonists Ro41-5253 and SB203580. Transwell studies were used to investigate whether DC-T cell direct contact was required for CLA expression. Single cell RNA sequencing (scRNAseq) of in vitro activated T cells was undertaken, with feature barcode antibody labelling of β7 and CLA. Differential gene expression and pathway analysis was undertaken. Results DC-activated T cells contained both α4β7+ and CLA+ cells and included a dual tropic population co-expressing both markers. In contrast, antibody-activated T cells expressed α4β7 but did not express CLA unless RA receptor alpha (RARa) signalling was also inhibited. The DC-derived signals that allowed CLA expression were partially dependent on p38MAPK and required DC-T cell contact for optimal activity. A high frequency of dual tropic T cells produced IFNg or TNFa. ScRNAseq identified 270 genes differentially expressed (fold change <-2 or >+2, FDR<0.01) between α4β7+CLA+ and α4β7+CLA- T populations generated by DC stimulation. Expression of FUT7, a fucosyltransferase implicated in generation of the CLA moiety, was increased in the α4β7+CLA+ population and overall 27 pathways were significantly enriched (p<0.05) in this population, including intestinal immune networks and IBD. Ex vivo, CD4+ and CD8+ dual tropic T cells were found in peripheral blood and intestinal tissue. CD4+ dual tropic T cells were significantly increased in the colon of patients with IBD (p=0.03). Conclusion DC-derived signals acting via p38MAPK generate pro-inflammatory dual tropic T cells even in the presence of active RA signalling. CLA expression may act as an additional ligand in gut trafficking by binding to selectins on the inflamed vascular endothelium and has a potential role in both gut and skin inflammation in IBD.

Synergistic role of retinoic acid signaling and Gata3 during primitive choanae formation.

Developmental defects of primitive choanae, an anatomical path to connect the embryonic nasal and oral cavity, result in disorders called choanal atresia (CA), which are associated with many congenital diseases and require immediate clinical intervention after birth. Previous studies revealed that reduced retinoid signaling underlies the etiology of CA. In the present study, by using multiple mouse models which conditionally deleted Rdh10 and Gata3 during embryogenesis, we showed that Gata3 expression is regulated by retinoid signaling during embryonic craniofacial development and plays crucial roles for development of the primitive choanae. Interestingly, Gata3 loss of function is known to cause hypoparathyroidism, sensorineural deafness and renal disease (HDR) syndrome, which exhibits CA as one of the phenotypes in humans. Our model partially phenocopies HDR syndrome with CA, and is thus a useful tool for investigating the molecular and cellular mechanisms of HDR syndrome. We further uncovered critical synergy of Gata3 and retinoid signaling during embryonic development, which will shed light on novel molecular and cellular etiology of congenital defects in primitive choanae formation.

Retinoids promote penis development in sequentially hermaphroditic snails

Sexual systems are surprisingly diverse, considering the ubiquity of sexual reproduction. Sequential hermaphroditism, the ability of an individual to change sex, has emerged multiple times independently across the animal kingdom. In molluscs, repeated shifts between ancestrally separate sexes and hermaphroditism are generally found at the level of family and above, suggesting recruitment of deeply conserved mechanisms. Despite this, molecular mechanisms of sexual development are poorly known. In molluscs with separate sexes, endocrine disrupting toxins bind the retinoid X receptor (RXR), activating ectopic male development in females, suggesting the retinoid pathway as a candidate controlling sexual transitions in sequential hermaphrodites. We therefore tested the role of retinoic acid signaling in sequentially hermaphroditic Crepidula snails, which develop first into males, then change sex, maturing into females. We show that retinoid agonists induce precocious penis growth in juveniles and superimposition of male development in females. Combining RXR antagonists with retinoid agonists significantly reduces penis length in induced juveniles, while similar treatments using retinoic acid receptor (RAR) antagonists increase penis length. Transcripts of both receptors are expressed in the induced penis. Our findings therefore show that retinoid signaling can initiate molluscan male genital development, and regulate penis length. Further, we show that retinoids induce ectopic male development in multiple Crepidula species. Species-specific influence of conspecific induction of sexual transitions correlates with responsiveness to retinoids. We propose that retinoid signaling plays a conserved role in molluscan male development, and that shifts in the timing of retinoid signaling may have been important for the origins of sequential hermaphroditism within molluscs.

Role of Retinoic Acid Signaling, FGF Signaling and Meis Genes in Control of Limb Development.

The function of retinoic acid (RA) during limb development is still debated, as loss and gain of function studies led to opposite conclusions. With regard to limb initiation, genetic studies demonstrated that activation of FGF10 signaling is required for the emergence of limb buds from the trunk, with Tbx5 and RA signaling acting upstream in the forelimb field, whereas Tbx4 and Pitx1 act upstream in the hindlimb field. Early studies in chick embryos suggested that RA as well as Meis1 and Meis2 (Meis1/2) are required for subsequent proximodistal patterning of both forelimbs and hindlimbs, with RA diffusing from the trunk, functioning to activate Meis1/2 specifically in the proximal limb bud mesoderm. However, genetic loss of RA signaling does not result in loss of limb Meis1/2 expression and limb patterning is normal, although Meis1/2 expression is reduced in trunk somitic mesoderm. More recent studies demonstrated that global genetic loss of Meis1/2 results in a somite defect and failure of limb bud initiation. Other new studies reported that conditional genetic loss of Meis1/2 in the limb results in proximodistal patterning defects, and distal FGF8 signaling represses Meis1/2 to constrain its expression to the proximal limb. In this review, we hypothesize that RA and Meis1/2 both function in the trunk to initiate forelimb bud initiation, but that limb Meis1/2 expression is activated proximally by a factor other than RA and repressed distally by FGF8 to generate proximodistal patterning.

2046-P: Retinoic Acid Signaling in Pancreatic Endocrine Cells Regulates Islet Cell Specification

Diabetes is characterized by β cell death and/or dysfunction. Currently, one promising treatment option for patients with diabetes involves replenishing the body with β cells to restore glucose homeostasis. Despite great progress using in vitro differentiation protocols to generate human β cells from stem cell populations, there are still challenges associated with generating fully functional β cells. To improve this therapeutic strategy, my studies are focusing on defining the role of cell signaling pathways in pancreatic islet cell specification. Genetic studies in fish, mice, and humans have demonstrated that retinoic acid (RA) is broadly required for pancreas development; however, the role of RA signaling in pancreatic endocrine cell specification remains unclear. By examining the role of RA using in vivo endocrine-specific inhibition of RA signaling at critical time points during pancreas development, we demonstrate that inhibition of RA signaling in the endocrine progenitor population results in the generation fewer β and increased Δ cell genes by embryonic day (e)16.5. These defects persist after birth and are accompanied by overt hyperglycemia in the adult. Whole transcriptome analysis further indicates that cross-talk between RA signaling and the Wnt pathway is important for islet cell specification. In addition, we show that RA signaling is also important for human β cell specification. Together, these data demonstrate the importance of RA signaling in the endocrine progenitor population and provide a framework to more clearly define the mechanisms by which RA signaling directs endocrine cell fate in mice and humans. Future studies on the role of RA and its interacting pathways during pancreas development will better inform strategies to treat diabetes using cell replacement therapies. Disclosure D. Lorberbaum: None. L. Sussel: None. Funding American Diabetes Association (1-18-PDF-107 to D.L.)

Divergent roles of retinoic acid signaling in T regulatory cell function

Abstract Regulatory T cells (Tregs) modulate immune responses to maintain immune homeostasis. Retinoic acid (RA) signaling promotes Treg generation and stability. Paradoxically, we observed that dominant negative RA receptor α expressed only in donor T cells (DNRARαfl/flCD4Cre) dampened inflammation and graft-versus-host disease (GVHD), while increasing Tregs. We found that diminishing RA signaling significantly enhanced their in vitro suppressive capacity. In vivo the adoptive transfer of DNRARαfl/flCD4Cre Tregs at the time of transplant was significantly (p<0.01) more effective than wild type (WT) controls in ameliorating GVHD. Mechanistically, enhanced suppression was associated with elevated expression of suppressive (CTLA-4, GITR, CD39) and fitness (CD25, pSTAT5) markers. To evaluate the intrinsic requirement of RA signaling in Tregs, we generated transgenic mice with conditional DNRARα expression in Tregs (DNRARαfl/fl x Foxp3YFPCre). Surprisingly, the extent of ablation of RA signaling resulted in divergent phenotypes. Heterozygous ablation (DNRARαfl/wt) was permissive of enhanced Treg suppression. In striking contrast and unexpectedly, homozygous ablation (DNRARαfl/fl) impaired Treg suppressive function and caused multi-organ (lung, liver) autoimmunity in >90% of females and males by 3 months of age. Poor suppression is not cell intrinsic as DNRARαfl/fl Tregs isolated from mixed bone marrow chimeras of congenic WT and DNRARαfl/fl x Foxp3YFP Cre had enhanced function. Our studies indicate that RA signaling in Tregs can be targeted to prevent autoimmunity by enhancing Treg suppression or alternatively, promote antitumor responses by reducing Treg function.

Developmental regulatory system of ocular-side-specific asymmetric pigmentation in flounder: Critical role of retinoic acid signaling.

The body color of the Pleuronectiformes is bilaterally asymmetric between right and left halves, with a dark ocular-side and a white blind-side. This body color asymmetry develops by restricted differentiation of melanophores and xanthophores on the ocular-side during metamorphosis, accompanied by migration of one eye to the future ocular-side. In this study, we elucidated the developmental regulatory system of this lateralized pigmentation. We found that in flounder, Sox10-positive chromatophore progenitors appear bilaterally both in the ocular- and blind-side skin of metamorphosing larvae, and that those arriving at the ocular-side skin differentiate into gch2-positive chromatoblasts and then chromatophores. Transient exposure of metamorphosing larvae to retinoic acid (RA)-induced progenitors on the blind-side to differentiate into gch2-positive chromatoblasts. On the contrary, exposure to an RA receptor antagonist, BMS493, suppressed the differentiation of gch2-positive chromatoblasts on the ocular-side. Thus, we demonstrated that RA is essential for flounder chromatophore progenitors to differentiate into chromatoblasts. At the time of chromatoblast differentiation on the ocular-side, cyp26b1, which inactivates RA, was upregulated on the blind-side skin compared with the ocular-side. Therefore, we surmise that ocular-side-specific pigmentation is regulated by the inhibition of RA-signaling by cyp26b1 on the blind-side.

Retinoic acid signaling within pancreatic endocrine progenitors regulates mouse and human β cell specification.

Retinoic acid (RA) signaling is essential for multiple developmental processes, including appropriate pancreas formation from the foregut endoderm. RA is also required to generate pancreatic progenitors from human pluripotent stem cells. However, the role of RA signaling during endocrine specification has not been fully explored. In this study, we demonstrate that the disruption of RA signaling within the NEUROG3-expressing endocrine progenitor population impairs mouse β cell differentiation and induces ectopic expression of crucial δ cell genes, including somatostatin. In addition, the inhibition of the RA pathway in hESC-derived pancreatic progenitors downstream of NEUROG3 induction impairs insulin expression. We further determine that RA-mediated regulation of endocrine cell differentiation occurs through Wnt pathway components. Together, these data demonstrate the importance of RA signaling in endocrine specification and identify conserved mechanisms by which RA signaling directs pancreatic endocrine cell fate.

Retinoic Acid Signaling Regulates the Metamorphosis of Feather Stars (Crinoidea, Echinodermata): Insight into the Evolution of the Animal Life Cycle.

Many marine invertebrates have a life cycle with planktonic larvae, although the evolution of this type of life cycle remains enigmatic. We recently proposed that the regulatory mechanism of life cycle transition is conserved between jellyfish (Cnidaria) and starfish (Echinoderm); retinoic acid (RA) signaling regulates strobilation and metamorphosis, respectively. However, the function of RA signaling in other animal groups is poorly understood in this context. Here, to determine the ancestral function of RA signaling in echinoderms, we investigated the role of RA signaling during the metamorphosis of the feather star, Antedon serrata (Crinoidea, Echinodermata). Although feather stars have different larval forms from starfish, we found that exogenous RA treatment on doliolaria larvae induced metamorphosis, like in starfish. Furthermore, blocking RA synthesis or binding to the RA receptor suppressed metamorphosis. These results suggested that RA signaling functions as a regulator of metamorphosis in the ancestor of echinoderms. Our data provides insight into the evolution of the animal life cycle from the viewpoint of RA signaling.

Manipulation of retinoic acid signaling in the nucleus accumbens shell alters rat emotional behavior

Novel targets for depression and anxiety disorders are necessary for the development of more effective pharmacotherapeutics. Our previous study found that the retinoic acid (RA) signaling pathway is the signaling pathway most enhanced in the nucleus accumbens (NAc) shell, a region important for depression, anxiety, and addiction. Genetic manipulations of RA signaling in the NAc affecting addiction-related behavior prompted our study of the role of retinoic acid signaling in depression-related and anxiety-related behavior using in vivo RNA interference. Knockdown of the retinoic acid degradation enzyme cytochrome p450 family 26 subfamily b member 1 (Cyp26b1) in the nucleus accumbens shell increased depression-related behavior while decreasing anxiety-like behavior. Knockdown of the retinoic acid binding protein, cellular RA binding protein 2 (Crabp2), also increased depression-related behavior. Knockdown of another RA binding partner fatty acid binding protein 5 (Fabp5), did not alter these behaviors. These results further support the contention that RA signaling in the NAc shell can affect emotional behavior and that targeting some components of this pathway could be a promising avenue for developing novel treatments for depression and anxiety.

Retinoic acid signaling in ovarian folliculogenesis and steroidogenesis

Retinoids are essential for reproduction. Most research has focused on the role of retinoic acid signaling in the regulation of meiosis during early fetal germ cell development. However, less attention has been paid to the possible effects of retinoic acid signaling in adult female gonads. Retinoic acid, its receptors, and the key enzymes required for retinoic acid synthesis are expressed in the ovaries and they are involved in the regulation of folliculogenesis and steroidogenesis. Exposure to compounds that can interfere with normal retinoic acid signaling is associated with adverse ovarian outcomes, including altered steroidogenesis and reduction in indicators of ovarian reserve in women and laboratory animal models. These observations call for more attention to retinoids as regulators of adult ovarian physiology and as possible targets of endocrine disruption by environmental chemicals. In this review, we summarize the current knowledge of retinoids in folliculogenesis and steroidogenesis in post-pubertal mammalian ovaries.

The genome of the giant Nomura\u2019s jellyfish sheds light on the early evolution of active predation

BackgroundUnique among cnidarians, jellyfish have remarkable morphological and biochemical innovations that allow them to actively hunt in the water column and were some of the first animals to become free-swimming. The class Scyphozoa, or true jellyfish, are characterized by a predominant medusa life-stage consisting of a bell and venomous tentacles used for hunting and defense, as well as using pulsed jet propulsion for mobility. Here, we present the genome of the giant Nomura’s jellyfish (Nemopilema nomurai) to understand the genetic basis of these key innovations.ResultsWe sequenced the genome and transcriptomes of the bell and tentacles of the giant Nomura’s jellyfish as well as transcriptomes across tissues and developmental stages of the Sanderia malayensis jellyfish. Analyses of the Nemopilema and other cnidarian genomes revealed adaptations associated with swimming, marked by codon bias in muscle contraction and expansion of neurotransmitter genes, along with expanded Myosin type II family and venom domains, possibly contributing to jellyfish mobility and active predation. We also identified gene family expansions of Wnt and posterior Hox genes and discovered the important role of retinoic acid signaling in this ancient lineage of metazoans, which together may be related to the unique jellyfish body plan (medusa formation).ConclusionsTaken together, the Nemopilema jellyfish genome and transcriptomes genetically confirm their unique morphological and physiological traits, which may have contributed to the success of jellyfish as early multi-cellular predators.

Myofibroblasts acquire retinoic acid–producing ability during fibroblast-to-myofibroblast transition following kidney injury

Tubular injury and interstitial fibrosis are the hallmarks of chronic kidney disease. While recent studies have verified that proximal tubular injury triggers interstitial fibrosis, the impact of fibrosis on tubular injury and regeneration remains poorly understood. We generated a novel mouse model expressing diphtheria toxin receptor on renal fibroblasts to allow for the selective disruption of renal fibroblast function. Administration of diphtheria toxin induced upregulation of the tubular injury marker Ngal and caused tubular proliferation in healthy kidneys, whereas administration of diphtheria toxin attenuated tubular regeneration in fibrotic kidneys. Microarray analysis revealed down-regulation of the retinol biosynthesis pathway in diphtheria toxin-treated kidneys. Healthy proximal tubules expressed retinaldehyde dehydrogenase 2 (RALDH2), a rate-limiting enzyme in retinoic acid biosynthesis. After injury, proximal tubules lost RALDH2 expression, whereas renal fibroblasts acquired strong expression of RALDH2 during the transition to myofibroblasts in several models of kidney injury. The retinoic acid receptor (RAR) RARγ was expressed in proximal tubules both with and without injury, and αB-crystallin, the product of an RAR target gene, was strongly expressed in proximal tubules after injury. Furthermore, BMS493, an inverse agonist of RARs, significantly attenuated tubular proliferation invitro. In human biopsy tissue from patients with IgA nephropathy, detection of RALDH2 in the interstitium correlated with older age and lower kidney function. These results suggest a role of retinoic acid signaling and cross-talk between fibroblasts and tubular epithelial cells during tubular injury and regeneration, and may suggest a beneficial effect of fibrosis in the early response to injury.

The Thalamus Regulates Retinoic Acid Signaling and Development of Parvalbumin Interneurons in Postnatal Mouse Prefrontal Cortex.

GABAergic inhibitory neurons in the prefrontal cortex (PFC) play crucial roles in higher cognitive functions. Despite the link between aberrant development of PFC interneurons and a number of psychiatric disorders, mechanisms underlying the development of these neurons are poorly understood. Here we show that the retinoic acid (RA)-degrading enzyme CYP26B1 (cytochrome P450 family 26, subfamily B, member 1) is transiently expressed in the mouse frontal cortex during postnatal development, and that medial ganglionic eminence (MGE)-derived interneurons, particularly in parvalbumin (PV)-expressing neurons, are the main cell type that has active RA signaling during this period. We found that frontal cortex-specific Cyp26b1 knock-out mice had an increased density of PV-expressing, but not somatostatin-expressing, interneurons in medial PFC, indicating a novel role of RA signaling in controlling PV neuron development. The initiation of Cyp26b1 expression in neonatal PFC coincides with the establishment of connections between the thalamus and the PFC. We found that these connections are required for the postnatal expression of Cyp26b1 in medial PFC. In addition to this region-specific role in postnatal PFC that regulates RA signaling and PV neuron development, the thalamocortical connectivity had an earlier role in controlling radial dispersion of MGE-derived interneurons throughout embryonic neocortex. In summary, our results suggest that the thalamus plays multiple, temporally separate roles in interneuron development in the PFC.