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bioRxiv2019

The protein repertoire in early vertebrate embryogenesis

We present an unprecedentedly comprehensive characterization of protein dynamics across early development in Xenopus laevis, available immediately via a convenient Web portal. This resource allows interrogation of the protein expression data in conjunction with other data modalities such as genome wide mRNA expression. This study provides detailed data for absolute levels of [~]14K unique Xenopus proteins representing homologues of [~]9K unique human genes - a rich resource for developmental biologists. The purpose of this manuscript is limited to presenting and releasing the data browser.\n\nHighlightsO_LIRelative protein expression from stage IV oocyte, blastula, gastrula, neurula, and early organogenesis\nC_LIO_LIBiological triplicates with confidence intervals on protein expression reflect certainty in dynamic patterns\nC_LIO_LIConvenient time-series Web-browser integrated with the multi-media Xenbase portal\nC_LIO_LIGene-symbol search and multi-gene protein/mRNA juxtaposition capabilities\nC_LI

developmental biology↗

bioRxiv2019

Fenestrae-associated protein Plvap regulates the rate of blood-borne proteins passage into the hypophysis

To maintain body homeostasis, endocrine systems must detect and integrate a multitude of blood-borne peripheral signals. This is mediated by specialized permeable pores in the endothelial membrane, dubbed fenestrae. Plasmalemma vesicles-associated protein (Plvap) is located in the fenestral diaphragm and is thought play a role in the selective passage of proteins through the fenestrae. However, this suggested function has yet to be demonstrated directly. Here, we studied the development of fenestrated capillaries in a major neuroendocrine interface between the blood and brain, namely the hypophysis. Using a transgenic permeability biosensor to visualize the vascular excretion of a genetically tagged plasma protein (DBP-EGFP), we show that the developmental acquisition of vascular permeability is associated with differential expression of zebrafish plvap orthologs in the hypophysis versus brain. Ultrastructural analysis of the hypophyseal vasculature revealed that plvapb mutants display deficiencies in fenestral and stomatal diaphragms as well as increased density of fenestrae, but not of caveolae. Measurements of DBP-EGFP dynamics in live plvapb mutant larvae provided a direct proof that Plvap limits the rate of blood-borne protein passage through fenestrated endothelia. Overall, we present the regulatory role of Plvap in the development of blood-borne protein detection machinery in a major neuroendocrine interface between the brain and the general circulation.

developmental biology↗

bioRxiv2019

An atlas of anterior hox gene expression in the embryonic sea lamprey head: hox-code evolution in vertebrates

In the hindbrain and the adjacent cranial neural crest (NC) cells of jawed vertebrates (gnathostomes), nested and segmentally-restricted domains of Hox gene expression provide a combinatorial Hox-code for specifying regional properties during head development. Extant jawless vertebrates, such as the sea lamprey (Petromyzon marinus), can provide insights into the evolution and diversification of this Hox-code in vertebrates. There is evidence for gnathostome-like spatial patterns of Hox expression in lamprey; however, the expression domains of the majority of lamprey hox genes from paralogy groups (PG) 1-4 are yet to be characterized, so it is unknown whether they are coupled to hindbrain segments (rhombomeres) and NC. In this study, we systematically describe the spatiotemporal expression of all 14 sea lamprey hox genes from PG1-PG4 in the developing hindbrain and pharynx to investigate the extent to which their expression conforms to the archetypal gnathostome hindbrain and pharyngeal hox-codes. We find many similarities in Hox expression between lamprey and gnathostome species, particularly in rhombomeric domains during hindbrain segmentation and in the cranial neural crest, enabling inference of aspects of Hox expression in the ancestral vertebrate embryonic head. These data are consistent with the idea that a Hox regulatory network underlying hindbrain segmentation is a pan vertebrate trait. We also reveal differences in hindbrain domains at later stages, as well as expression in the endostyle and in pharyngeal arch (PA) 1 mesoderm. Our analysis suggests that many Hox expression domains that are observed in extant gnathostomes were present in ancestral vertebrates but have been partitioned differently across Hox clusters in gnathostome and cyclostome lineages after duplication.

developmental biology↗

bioRxiv2019

The Developmental Transcriptome for Lytechinus variegatus Exhibits Temporally Punctuated Gene Expression Changes

Embryonic development is arguably the most complex process an organism undergoes during its lifetime, and understanding this complexity is best approached with a systems-level perspective. The sea urchin has become a highly valuable model organism for understanding developmental specification, morphogenesis, and evolution. As a non-chordate deuterostome, the sea urchin occupies an important evolutionary niche between protostomes and vertebrates. Lytechinus variegatus (Lv) is an Atlantic species that has been well studied, and which has provided important insights into signal transduction, patterning, and morphogenetic changes during embryonic and larval development. The Pacific species, Strongylocentrotus purpuratus (Sp), is another well-studied sea urchin, particularly for gene regulatory networks (GRNs) and cis-regulatory analyses. A well-annotated genome and transcriptome for Sp are available, but similar resources have not been developed for Lv. Here, we provide an analysis of the Lv transcriptome at 11 timepoints during embryonic and larval development. The data indicate that the gene regulatory networks that underlie specification are well-conserved among sea urchin species. We show that the major transitions in variation of embryonic transcription divide the developmental time series into four distinct, temporally sequential phases. Our work shows that sea urchin development occurs via sequential intervals of relatively stable gene expression states that are punctuated by abrupt transitions.

developmental biology↗

bioRxiv2019

Constrained Transcriptional Polarity In The Organization Of Mammalian Hox Gene Clusters

In many animal species with a bilateral symmetry, Hox genes are clustered either at one or at several genomic loci. This organization has a functional relevance, as the transcriptional control applied to each gene depends upon its relative position within the gene cluster. It was previously noted that vertebrate Hox clusters display a much higher level of genomic organization than their invertebrate counterparts. The former are always more compact than the latter, they are generally devoid of repeats and of interspersed genes, and all genes are transcribed by the same DNA strand, suggesting that particular factors constrained these clusters towards a tighter structure during the evolution of the vertebrate lineage. Here we investigate the importance of uniform transcriptional orientation by engineering several alleles within the HoxD cluster such as to invert one or several transcription unit(s), with or without a neighboring CTCF site. We observe that the association between the tight structure of mammalian Hox clusters and their regulation makes inversions likely detrimental to the proper implementation of this complex genetic system. We propose that the consolidation of Hox clusters in vertebrates, including transcriptional polarity, evolved in conjunction with the emergence of global gene regulation via the flanking regulatory landscapes, to optimize a coordinated response of selected subsets of target genes in cis.

developmental biology↗

bioRxiv2019

PRDM16 establishes lineage-specific transcriptional program to promote temporal progression of neural progenitors in the mouse neocortex

Radial glia (RG) in the neocortex sequentially generate distinct subtypes of projection neurons, accounting for the diversity and complex assembly of cortical neural circuits. Mechanisms that drive the rapid and precise temporal progression of RG are beginning to be elucidated. Here we reveal that the RG-specific transcriptional regulator PRDM16 promotes the transition of early to late phases of neurogenesis in the mouse neocortex. Prdm16 mutant RG delays the timely progression of RG, leading to defective cortical laminar organization. We show that PRDM16 regulates expression of neuronal specification genes and a subset of genes that are dynamically expressed between mid-and late-neurogenesis. Our genomic analysis suggests that PRDM16 suppresses target gene expression through maintaining chromatin accessibility of permissive enhancers. Altogether, our results demonstrate a critical role of PRDM16 in establishing stage-specific gene expression program of RG during cortical neurogenesis. These findings also support a model where progenitor cells are primed with daughter cell gene expression program for rapid cell differentiation.

developmental biology↗

bioRxiv2019

A pivotal genetic program controlled by thyroid hormone during the maturation of GABAergic neurons in mice

In mammals, brain development is critically dependent on proper thyroid hormone signaling, via the TR1 nuclear receptor. However, the downstream mechanisms by which TR1 impacts brain development are currently unknown, notably because this receptor is expressed ubiquitously from early stages of development. In order to better define the function of TR1 in the developing brain, we used mouse genetics to induce the expression of a dominant-negative mutation of the receptor specifically in GABAergic neurons, the main inhibitory neurons in the brain, which were previously identified as sensitive to hypothyroidism. This triggered post-natal epileptic seizures, reflecting a profound impairment of GABAergic neuron maturation in different brain areas. Analysis of transcriptome and TR1 cistrome also allowed us to identify a small set of genes, the transcription of which is upregulated by TR1 in GABAergic neurons during post-natal maturation of the striatum and which probably play an important role during neurodevelopment. Thus, our results point to GABAergic neurons as direct targets of thyroid hormone during brain development and suggest that many defects seen in hypothyroid brains may be secondary to GABAergic neuron malfunction.

developmental biology↗

bioRxiv2019

Satb2 regulates proliferation and nuclear integrity of pre-osteoblasts

Special AT-rich sequence binding protein 2 (Satb2) is a matrix attachment region (MAR) binding protein. Satb2 impacts skeletal development by regulating gene transcription required for osteogenic differentiation. Although its role as a high-order transcription factor is well supported, other roles for Satb2 in skeletal development remain unclear. In particular, the impact of dosage sensitivity (heterozygous mutations) and variance on phenotypic severity is still not well understood. To further investigate molecular and cellular mechanisms of Satb2-mediated skeletal defects, we used the CRISPR/Cas9 system to generate Satb2 mutations in MC3T3-E1 cells. Our data suggest that, in addition to its role in differentiation, Satb2 regulates progenitor proliferation. We also find that mutations in Satb2 cause chromatin defects including nuclear blebbing and donut-shaped nuclei. These defects may contribute to a slight increase in apoptosis in mutant cells, but apoptosis is insufficient to explain the proliferation defects. Satb2 expression exhibits population-level variation and is mostly highly expressed from late G1 to late G2. Based on these data, we hypothesize that Satb2 may regulate proliferation through two separate mechanisms. First, Satb2 may regulate the expression of genes necessary for cell cycle progression in pre-osteoblasts. Second, similar to other MAR-binding proteins, Satb2 may participate in DNA replication. Deficiencies in either of these processes could reduce the pace of cell cycle progression and contribute to nuclear damage. We also hypothesize that Satb2-mediated proliferation defects may be buffered in some genetic backgrounds, which provides some explanation for differences in severity of skeletal defects. Further elucidation of the role of Satb2 in proliferation has potential impacts on our understanding of both skeletal defects and cancer.

developmental biology↗

bioRxiv2019

Multi-enhancer transcriptional hubs confer phenotypic robustness

We had previously shown in Drosophila melanogaster embryos that low-affinity Ultrabithorax (Ubx)-responsive shavenbaby (svb) enhancers drive robust expression using localized transcriptional environments and that active svb enhancers tended to colocalize, even when placed on different chromosomes (Tsai et al., 2017). Here, we test the hypothesis that these multi-enhancer \"hubs\" improve robustness by increasing transcription factor retention near transcription sites. Deleting a redundant enhancer from the svb locus led to reduced trichome numbers in embryos raised at elevated temperatures. Using high-resolution fluorescence microscopy, we observed lower Ubx concentration and transcriptional output in this deletion allele. Transcription sites of the full svb cis-regulatory region inserted into a different chromosome colocalized with the svb locus, increasing Ubx concentration, the transcriptional output of svb, and partially rescuing the phenotype. Thus, multiple enhancers could reinforce a local transcriptional hub to buffer against environmental stresses and genetic perturbations, providing a mechanism for phenotypical robustness.\n\nImpact statementMultiple enhancers in physical proximity can reinforce shared transcriptional \"hubs\" to retain transcription factors, providing a buffer during environmental stresses and genetic perturbations to preserve phenotypic robustness.

developmental biology↗

bioRxiv2019

Lumen expansion facilitates epiblast-primitive endoderm fate specification in the mouse blastocyst formation.

Mouse blastocyst formation involves lumen formation and cell fate specification. While many studies have investigated how the blastocyst cell lineages are specified through genetics and signaling, studies into the potential role of the fluid lumen have yet to be conducted. We discover that blastocyst fluid emerges by secretion of cytoplasmic vesicles to intercellular space in addition to trans-epithelial flow. We observe that the beginning of epiblast and primitive endoderm spatial segregation directly follows lumen coalescence. Notably, we show that perturbing lumen expansion by pharmacological and biophysical means impair the specification and spatial segregation of primitive endoderm cells within the blastocyst. Combined, our results suggest that blastocyst lumen expansion plays a critical role in guiding cell fate specification and positioning. As epithelial tissues typically form lumina, lumen expansion may provide a general mechanism of cell fate control in many tissues.

developmental biology↗

bioRxiv2019

Pax9 is required for cardiovascular development and interacts with Tbx1 in the pharyngeal endoderm to control 4th pharyngeal arch artery morphogenesis.

Developmental defects affecting the heart and aortic arch arteries are a key phenotype observed in DiGeorge syndrome patients and are caused by a microdeletion on chromosome 22q11. Heterozygosity of TBX1, one of the deleted genes, is expressed throughout the pharyngeal arches and is considered a key component for the arch artery defects. Pax9 is expressed in the pharyngeal endoderm and is downregulated in Tbx1 mutant mice. We show here that Pax9 deficient mice are born with complex cardiovascular malformations affecting the outflow tract and aortic arch arteries with failure of the 3rd and 4th pharyngeal arch arteries to form correctly. Transcriptome analysis indicated that Pax9 and Tbx1 may function together, and mice double heterozygous for Tbx1/Pax9 presented with a significantly increased incidence of interrupted aortic arch when compared to Tbx1 heterozygous mice. Using a novel Pax9Cre allele we demonstrated that the site of this Tbx1-Pax9 genetic interaction is in the pharyngeal endoderm, therefore revealing that a Tbx1/Pax9-controlled signalling mechanism emanating from the pharyngeal endoderm is required for critical tissue interactions during normal morphogenesis of the pharyngeal arch artery system.\n\nSummary statementPax9 is required for outflow tract and aortic arch development, and functions together with Tbx1 in the pharyngeal endoderm for 4th arch artery formation.

developmental biology↗

bioRxiv2019

The transcription factor Odd-paired regulates temporal identity in transit-amplifying neural progenitors via an incoherent feed-forward loop

Neural progenitors undergo temporal patterning to generate diverse neurons in a chronological order. This process is well-studied in the developing Drosophila brain and conserved in mammals. During larval stages, intermediate neural progenitors (INPs) serially express Dichaete (D), grainyhead (Grh) and eyeless (Ey/Pax6), but how the transitions are regulated is not precisely understood. Here, we developed a method to isolate transcriptomes of INPs in their distinct temporal states to identify a complete set of temporal patterning factors. Our analysis identifies odd-paired (opa), as a key regulator of temporal patterning. Temporal patterning is initiated when the SWI/SNF complex component Osa induces D and its repressor Opa at the same time but with distinct kinetics. Then, high Opa levels repress D to allow Grh transcription and progress to the next temporal state. We propose that Osa and its target genes opa and D form an incoherent feedforward loop (FFL) and a new mechanism allowing the successive expression of temporal identities.

developmental biology↗

bioRxiv2019

HDAC6 promotes PMA-induced megakaryocyte differentiation of K562 cells by regulating ROS levels via NOX4 and repressing Glycophorin A

The human erythroleukemia (K562) cells are considered as bipotent megakaryocyte-erythroid progenitor cells and the differentiation of these cells to megakaryocytes (MK) in the presence of phorbol 12-myristate 13-acetate (PMA) mimics in vivo differentiation of MEP (megakaryocyte-erythroid progenitor) cells in the bone marrow. Histone deacetylases (HDACs) are involved in gene suppression and their roles during the MK differentiation remains largely undefined. In the present study, we have studied the expression levels of class I and class II HDACs during phorbol 12-myristate 13-acetate (PMA)-induced differentiation of K562 cells to MK. Class IIb HDACs (HDAC6 & HDAC10) were significantly up regulated time dependently upto 4 days of PMA-induced MK differentiation along with decreased acetylation levels of H3K9 and H3K56. Pharmacological inhibition and knockdown studies of HDAC6 using tubastatin A (TubA) and shRNA-HDAC6 respectively, during MK differentiation resulted in down regulation of MK lineage marker CD61 and up regulation of erythroid lineage gene glycophorin A (GYPA). HDAC6 over expression in K562 cells showed significant up regulation of CD61, MK transcription factors (FOG1 and GATA2) and down regulation of GYPA. ChIP-PCR studies showed enrichment of HDAC6 protein on GYPA promoter during differentiation indicating GYPA gene repression by HDAC6. Further studies on elucidating the role of HDAC6 in MK differentiation clearly indicated that HDAC6 is required for the production of sustainable levels of reactive oxygen species (ROS), an important regulator of MK differentiation, via NOX4.- ROS-HDAC6 circuit. In this study, we provide the first evidence that during PMA-induced megakaryocyte differentiation of K562 cells, HDAC6 represses erythroid lineage marker gene, GYPA, and promotes the sustainable levels of ROS via NOX4 required for MK differentiation.\n\nKey pointsO_LIHDAC6 upregulated during MK differentiation is involved in sustainable production of ROS via the circuit - HDAC6-NOX4-ROS-HDAC6.\nC_LIO_LIHDAC6 inhibits erythroid lineage gene, GYPA, by forming a repressor complex over the promoter region.\nC_LI

developmental biology↗

bioRxiv2019

Chemokine signaling links cell cycle progression and cilia formation for left-right symmetry breaking

Zebrafish dorsal forerunner cells (DFCs) undergo vigorous proliferation during epiboly and then exit cell cycle to generate Kupffers vesicle (KV), a ciliated organ necessary for establishing left-right (L-R) asymmetry. DFC proliferation defects are often accompanied by impaired cilia elongation in KV, but the functional and molecular interaction between cell-cycle progression and cilia formation remains unknown. Here we show that chemokine receptor Cxcr4a is required for L-R laterality by controlling DFC proliferation and KV ciliogenesis. Functional analysis revealed that Cxcr4a accelerates G1/S transition in DFCs and stabilizes Foxj1a, a master regulator of motile cilia, by stimulating Cyclin D1 expression through ERK1/2 signaling. Mechanistically, Cyclin D1-CDK4/6 drives G1/S transition during DFC proliferation and phosphorylates Foxj1a, thereby disrupting its association with Psmd4b, a 19S regulatory subunit. This prevents the ubiquitin-independent proteasomal degradation of Foxj1a. Our study uncovers a role for Cxcr4 signaling in L-R patterning and provides fundamental insights into the molecular linkage between cell-cycle progression and ciliogenesis.\n\nAuthor summaryDuring the organogenesis of zebrafish L-R organizer named KV, DFCs proliferate rapidly during epiboly and then exit the cell cycle to differentiate into ciliated epithelial KV cells. Cell cycle defects in DFCs are often accompanied by an alteration in KV cilia elongation. However, whether the cell cycle and cilia formation are mechanistically linked remains as an open question. In this study, we report that Cxcr4 signaling is required for DFC proliferation and KV ciliogenesis. We reveal that Cxcl12b/Cxcr4a signaling activates ERK1/2, which then promotes Cyclin D1 expression. Cyclin D1-CDK4/6 accelerates the G1/S transition in DFCs, while also facilitates cilia formation via stabilization of Foxj1a. Notably, Foxj1 undergoes proteasomal degradation via Ub-independent pathway during KV organogenesis. Our study further demonstrates that CDK4 phosphorylates and stabilizes Foxj1a by disrupting its association with Psmd4b, a 19S regulatory subunit. In summary, Cxcl12b/Cxcr4a chemokine signaling links cell cycle progression and cilia formation for L-R symmetry breaking via regulating Cyclin D1 expression.

developmental biology↗

bioRxiv2019

Fog signaling has diverse roles in epithelial morphogenesis in insects

The Drosophila Fog pathway represents one of the best-understood signaling cascades controlling epithelial morphogenesis. During gastrulation, Fog induces apical cell constrictions that drive the invagination of mesoderm and posterior gut primordia. The cellular mechanisms underlying primordia internalization vary greatly among insects and recent work has suggested that Fog signaling is specific to the fast mode of gastrulation found in some flies. On the contrary, here we show in the beetle Tribolium, whose development is broadly representative for insects, that Fog has multiple morphogenetic functions. It modulates mesoderm internalization and controls a massive posterior infolding involved in gut and extraembryonic development. In addition, Fog signaling affects blastoderm cellularization, primordial germ cell positioning and cuboidal-to-squamous cell shape transitions in the extraembryonic serosa. Comparative analyses with two other distantly related insect species reveals that Fogs role during cellularisation is widely conserved and therefore might represent the ancestral function of the pathway.

developmental biology↗

bioRxiv2019

Metabolic reprogramming from glycolysis to amino acid utilization in cardiac HIF1α deficient mice.

RationaleHypoxia is an important environmental cue implicated in several physiopathological processes, including heart development. Several mouse models of activation or inhibition of hypoxia have been previously described. While gain of function models have been extensively characterized and indicate that HIF1 signaling needs to be tightly regulated to ensure a proper cardiac development, there is lack of consensus in the field about the functional outcomes of HIF1 loss.\n\nObjectiveIn this study, we aim to assess the consequences of cardiac deletion of HIF1 during heart development and identify the cardiac adaptations to HIF1 loss.\n\nMethods and ResultsHere, we used a conditional deletion model of Hif1a in NKX2.5+ cardiac progenitors. By a combination of histology, electron microscopy, massive gene expression studies, proteomics, metabolomics and cardiac imaging, we found that HIF1 is dispensable for cardiac development. Hif1a loss results in glycolytic inhibition in the embryonic heart without affecting normal cardiac growth. However, together with a premature increase in mitochondrial number by E12.5, we found global upregulation of amino acid transport and catabolic processes. Interestingly, this amino acid catabolism activation is transient and does not preclude the normal cardiac metabolic switch towards fatty acid oxidation (FAO) after E14.5. Moreover, Hif1a loss is accompanied by an increase in ATF4, described as an important regulator of several amino acid transporters.\n\nConclusionsOur data indicate that HIF1 is not required for normal cardiac development and suggest that additional mechanisms can compensate Hif1a loss. Moreover, our results reveal the metabolic flexibility of the embryonic heart at early stages of development, showing the capacity of the myocardium to adapt its energy source to satisfy the energetic and building blocks demands to achieve normal cardiac growth and function. This metabolic reprograming might be relevant in the setting of adult cardiac failure.

developmental biology↗

bioRxiv2019

Embryonic geometry underlies phenotypic variation in decanalized conditions

During development, many mutations cause increased variation in phenotypic outcomes, a phenomenon termed decanalization. Such variations can often be attributed to genetic and environmental perturbations. However, phenotypic discordance remains even in isogenic model organisms raised in homogeneous environments. To understand the mechanisms underlying phenotypic variation, we used as a model the highly precise anterior-posterior (AP) patterning of the early Drosophila embryo. We decanalized the system by depleting the maternal bcd product and found that in contrast to the highly scaled patterning in the wild-type, the segmentation gene boundaries shift away from the scaled positions according to the total embryonic length. Embryonic geometry is hence a key factor predetermining patterning outcomes in such decanalized conditions. Embryonic geometry was also found to predict individual patterning outcomes under bcd overexpression, another decanalizing condition. Further analysis of the gene regulatory network acting downstream of the morphogen identified vulnerable points in the networks due to limitations in the available physical space.

developmental biology↗

bioRxiv2019

Homeostasis of the intervertebral disc requires regulation of STAT3 signaling by the adhesion G-protein coupled receptor ADGRG6

Degenerative changes of the intervertebral disc (IVD) are a leading cause of disability affecting humans worldwide. While this is primarily attributed to trauma and aging, genetic variation is associated with disc degeneration in humans. However, the precise mechanisms driving the initiation and progression of disease remain elusive due to a paucity of genetic animal models. Here, we discuss a novel genetic mouse model of endplate-oriented disc degeneration. We show that the adhesion G-protein coupled receptor G6 (ADGRG6) mediates several anabolic and catabolic factors, fibrotic collagen genes, pro-inflammatory pathways, and mechanical properties of the IVD, prior to the onset of overt histopathology of these tissues. Furthermore, we found increased IL-6/STAT3 activation in the IVD and demonstrate that treatment with a chemical inhibitor of STAT3 activation ameliorates disc degeneration in these mutant mice. These findings establish ADGRG6 as a critical regulator of homeostasis of adult disc homeostasis and implicate ADGRG6 and STAT3 as promising therapeutic targets for degenerative joint diseases.\n\nAuthor summaryDegenerative changes of the intervertebral disc (IVD) are a leading cause of disability affecting humans worldwide. While this is primarily attributed to trauma and aging, genetic variation is associated with disc degeneration in humans. However, the precise mechanisms driving the initiation and progression of disease remain elusive due to a paucity of genetic animal models. Here, we discuss a novel genetic mouse model of endplate-oriented disc degeneration. We show that the adhesion G-protein coupled receptor G6 (ADGRG6) mediates fibrotic collagen expression, causing increased mechanical stiffness of the IVD prior to the onset of histopathology in adult mice. Furthermore, we found increased IL-6/STAT3 activation in the IVD and demonstrate that treatment with a chemical inhibitor of STAT3 activation ameliorates disc degeneration in these mutant mice. Our results demonstrate that ADGRG6 regulation of STAT3 signaling is important for IVD homeostasis, indicating potential therapeutic targets for degenerative joint disorders.

developmental biology↗