Browse Articles

Reciprocal projections between the globus pallidus externa and cortex span motor and nonmotor regions

The globus pallidus externa (GPe) is a heterogeneous nucleus of the basal ganglia, with intricate connections to other basal ganglia nuclei, as well as direct connections to the cortex. The anatomic, molecular, and electrophysiologic properties of cortex-projecting pallidocortical neurons are not well characterized. Here, we show that pallidocortical neurons project to diverse motor and nonmotor cortical regions, are organized topographically in the GPe, and segregate into at least two distinct electrophysiological and molecular phenotypes. In addition, we find that the GPe receives direct synaptic input from deep layers of diverse motor and nonmotor cortical regions, some of which form reciprocal connections onto pallidocortical neurons. These results demonstrate the existence of a fast, bidirectional circuit between the GPe and the cortex that is ideally positioned to integrate information about behavioral goals, internal states, and environmental cues to rapidly modulate behavior.

Single-cell resolution uncovers neighboring cell subtypes that share steroidogenic capacity during fetal testis development

Historically, endocrine cells were perceived to coordinate their output in a uniform manner. Recently however, single-cell technologies have uncovered heterogeneity within these populations, indicating that individual cells may operate as independently regulated units. Using high-resolution tools such as single-molecule fluorescent in situ hybridization (sm-FISH) and single-cell RNA sequencing (scRNA-seq), we investigated the contributions of individual and the collective of fetal Leydig cells to androgen production over time during mouse testis development. Temporal profiles of intratesticular androgens alongside the expression of steroidogenic pathway genes ( Star, Cyp11a1, Cyp17a1, and Hsd3b1 ) from prenatal to perinatal testes demonstrated that the peak in gene expression preceded the peak in androgen production. Spatially, steroidogenic cells were initially observed to be concentrated toward the anterior–posterior poles along the center of the dorsal–ventral axis of the fetal testis at embryonic day (E) 13 and then expanded to a uniform distribution by E16. Next, sm-FISH using probes for individual steroidogenic pathway genes exposed the following findings: gene transcription and processing of individual and combinations of steroidogenic pathway genes are not synchronized among fetal Leydig cells; and some fetal Leydig cells express incomplete sets of genes. Further, sm-FISH and scRNA-seq data corroborated the presence of fetal Leydig and other interstitial cell types harboring incomplete sets of steroidogenic pathway genes throughout developmental stages. Taken together, these findings highlight that fetal steroidogenic gene expression is tightly regulated and that transcript presence among interstitial cell types promotes the possibility that optimal androgen biosynthesis results from a cooperative effort among neighboring steroidogenic cells.

Increasing boreal fires reduce future global warming and sea ice loss

Biomass burning can affect climate via the emission of aerosols and their subsequent impact on radiation, cloud microphysics, and surface and atmospheric albedo. Biomass burning emissions (BBEs) over the boreal region have strongly increased during the last decade and are expected to continue increasing as the climate warms. Climate models simulate aerosol processes, yet historical and future Coupled Model Intercomparison Project (CMIP) simulations have no active fire component, and BBEs are prescribed as external forcings. Here, we show that CMIP6 used future boreal BBEs scenarios with unrealistic near-zero trends that have a large impact on climate trends. By running sensitivity experiments with ramped up boreal emissions based on observed trends, we find that increasing boreal BBEs reduces global warming by 12% and Arctic warming by 38%, reducing the loss of sea ice. Tropical precipitation shifts southward as a result of the hemispheric difference in boreal aerosol forcing and subsequent temperature response. These changes stem from the impact of aerosols on clouds, increasing cloud droplet number concentration, cloud optical depth, and low cloud cover, ultimately reducing surface shortwave flux over northern latitudes. Our results highlight the importance of realistic boreal BBEs in climate model simulations and the need for improved understanding of boreal emission trends and aerosol–climate interactions.

Multiple cortical systems influence a single vibrissa muscle

What is the neural substrate that enables the cerebral cortex to control a single mystacial vibrissa and orchestrate its movement? To answer this question, we injected rabies virus into the intrinsic muscle that protracts the rat C3 vibrissa and used retrograde transneuronal transport to identify the cortical neurons that influence the muscle. A surprisingly diverse set of cortical areas is the origin of disynaptic control over the motoneurons that influence the C3 protractor. More than two thirds of these layer 5 pyramidal neurons (L5PNs) are dispersed in frontal and parietal areas outside the primary motor cortex (vM1). This observation emphasizes the importance of descending motor commands from non-primary motor areas. More than a third of the L5PNs originate from somatosensory areas, such as the barrel field (vS1). The barrel field has been long considered a prototypic model system for studying sensory processing at the level of the cerebral cortex. Even so, we find that the number of L5PNs in vS1, and even their peak density, rivals the number and peak density of L5PNs in vM1. Thus, our results emphasize the importance of the barrel field in processing motor output. The distribution of L5PNs in vM1 and vS1 leads us to propose a model of vibrissa protraction in which vM1 output results in protraction, and vS1 output results in reciprocal inhibition (suppression) of protraction. This paired initiation and suppression of complementary movements may be a general feature of the descending output from the rodent M1 and S1.

Convergent expansions of keystone gene families drive metabolic innovation in Saccharomycotina yeasts

Many remarkable phenotypes have repeatedly occurred across vast evolutionary distances. When convergent traits emerge on the tree of life, they are sometimes driven by the same underlying gene families, while other times, many different gene families are involved. Conversely, a gene family may be repeatedly recruited for a single trait or many different traits. To understand the general rules governing convergence at both genomic and phenotypic levels, we systematically tested associations between 56 binary metabolic traits and gene count in 14,785 gene families from 993 Saccharomycotina yeasts. Using a recently developed phylogenetic approach that reduces spurious correlations, we found that gene family expansion and contraction were significantly linked to trait gain and loss in 45/56 (80%) traits. While 595/739 (81%) significant gene families were associated with only one trait, we also identified several “keystone” gene families that were significantly associated with up to 13/56 (23%) of all traits. Strikingly, most of these families are known to encode metabolic enzymes and transporters, including all members of the industrially relevant MAL tose fermentation loci in the baker’s yeast Saccharomyces cerevisiae . These results indicate that convergent evolution on the gene family level may be more widespread across deeper timescales than previously believed.

Revealing land control dynamics in emerging agricultural frontiers

The expansion of commodity agriculture into tropical and subtropical woodlands degrades ecosystem functionality, biodiversity, and the livelihood base of millions of people. Understanding where and how agricultural frontiers emerge is thus important. Yet, existing monitoring approaches typically focus on mapping deforestation and do not capture the shifts in land access and ownership that lay the ground for agricultural expansion, thereby missing early stages of frontier development. We develop an approach that captures these early dynamics and apply it to the entire 1,1 million km 2 of the Chaco, a global deforestation hotspot. Through the detection of linear features indicative of land claims and the analysis of their spatial–temporal dynamics, we reveal that the footprint of agricultural frontiers in the region extends far beyond that of deforestation. Most of the Chaco shows signs of land claiming, and although claiming activity is especially concentrated close to active deforestation, emergent claiming in remote parts of the Bolivian and Paraguayan Chaco indicates rapidly growing interest in land in these regions. Finally, the strong spatial correlation between land claiming and the disappearance of smallholder homesteads points to the social repercussions of early agricultural frontier expansion in the Chaco. By offering a transferable template to map land-control indicators at scale, our approach enables a better understanding of frontier processes and more accurate targeting of policy interventions in emerging agricultural frontiers globally.

Fine ash from the Campanian Ignimbrite super-eruption, ~ 40 ka, southern Italy: implications for dispersal mechanisms and health hazard

Abstract Super-eruptions disperse volcanic ash over vast areas, impacting the environment and human health. Fine ash, particularly its respirable fraction (< 4 µm), poses a significant health hazard by inhalation due to its high dispersal potential. Understanding the aerodynamic properties but also composition of ash particles is fundamental to constrain dispersal and deposition mechanisms in both proximal and distal environments. Current atmospheric dispersal models rely on empirical drag equations calibrated with geometric shape descriptors. However, these models often overlook the effects of the actual particle density, as a uniform componentry is typically assumed. In addition, particles have variable shapes but such data from super-eruptions remains limited and no standardized measurement methods exist. Here, we determine the terminal fall velocity (v t ) of fine ash from the Campanian Ignimbrite super-eruption (~ 40 ka, Campi Flegrei), by evaluating the components and particle shapes from proximal to ultra-distal locations. To verify the attribution of the proximal sample to the CI eruption, a 40Ar/39Ar dating was performed, allowing its correlation with the ultra-distal deposits. Results show that, due to the influence of shape and density, glass particles exhibit lower v t compared to mineral phases (v t, feldspar/v t, glass = 1.05 ± 0.03, v t, SiO2/v t, glass = 1.09 ± 0.02), enabling greater travel distances. Drag equations accounting for measured particle shapes differ significantly from spherical approximations. The spherical model overestimation of v t highlights the necessity of shape-specific models to produce more accurate dispersal predictions. Extremely low v t (< 0.1 cm/s) for respirable ash fraction, which indicates prolonged atmospheric suspension and long-time resuspension potential, along with the presence of cristobalite, lead to important implications for health hazards. These findings further enhance our understanding of volcanic ash aerodynamic behaviour and the far-reaching impact of super-eruptions.

Symmetries and synchronization from whole-neural activity in the <i>Caenorhabditis elegans</i> connectome: Integration of functional and structural networks

Understanding the dynamical behavior of complex systems from their underlying network architectures is a long-standing question in complexity theory. Therefore, many metrics have been devised to extract network features like motifs, centrality, and modularity measures. It has previously been proposed that network symmetries are of particular importance since they are expected to underlie the synchronization of a system’s units, which is ubiquitously observed in nervous system activity patterns. However, perfectly symmetrical structures are difficult to assess in noisy measurements of biological systems, like neuronal connectomes. Here, we devise a principled method to infer network symmetries from combined connectome and neuronal activity data. Using nervous system-wide population activity recordings of the Caenorhabditis elegans backward locomotor system, we infer structures in the connectome called fibration symmetries, which can explain which group of neurons synchronize their activity. Our analysis suggests functional building blocks in the animal’s motor periphery, providing testable hypotheses on how descending interneuron circuits communicate with the motor periphery to control behavior. Our approach opens a door to exploring the structure–function relations in other complex systems, like the nervous systems of larger animals.

Diagnostic accuracy of dual energy computed tomography for suspected pyogenic spondylodiscitis

Abstract While magnetic resonance imaging (MRI) is the diagnostic method of choice, we here analyze the diagnostic potential of dual-energy computed tomography (DECT) in differentiating abnormal discs from normal-appearing discs and in differentiating between infectious and degenerative conditions. Twenty-eight patients with suspected spondylodiscitis who underwent DECT and MRI of the spine were retrospectively included. Eighteen patients were diagnosed with spondylodiscitis and ten patients with degenerative disc disease. A combined clinical reference standard for the diagnosis was used. One abnormal disc and one normal-appearing disc per patient were included. Three blinded readers analyzed CT, DECT cMaps and MRI images. Quantitative analysis was performed in standardized regions of interest placed in each of the two discs included. Mixed-model analysis was used to identify correlations between CT density alterations and spondylodiscitis or degenerative disc disease. Diagnostic accuracy for differentiating abnormal discs and normal-appearing discs: 69.7% (95% CI, 56.0 to 81.2) for CT, 76.8% (95% CI, 63.6 to 87.0) for CT + DECT, 58.9% (95% CI, 45.0 to 71.9) for MRI; for differentiating spondylodiscitis and degenerative disc disease: 64.3% (95% CI, 44.1 to 81.4) for CT, 60.7% (95% CI, 40.6 to 78.5) for CT + DECT, 53.6% (95% CI, 33.9 to 72.5) for MRI. Mixed-model analysis revealed that normal-appearing discs had higher average density than abnormal discs in DECT (mean difference = 47.0 HU (95% CI, 32.8 to 61.3), p = &lt; 0.001). In summary, both qualitative and quantitative DECT can distinguish normal-appearing discs from abnormal discs. Spondylodiscitis and degenerative disc disease were not distinguished accurately by DECT in this study.

In-plane ferroelectricity with high Curie temperatures in nonequilibrium SnSe _1-x S _x van der Waals semiconductors

While symmetry breaking in 2D ferroelectrics is obviously linked to the single-layer structure, layered (van der Waals) ferroelectrics can have a multitude of underlying mechanisms, making their identification nontrivial and often controversial. This complexity is exemplified by tin chalcogenides whose equilibrium structure, the orthorhombic α-phase with space group Pnma , includes an inversion center and which therefore should not be ferroelectric. Yet, recent work demonstrated polarization switching and ferroelectric domains in few-layer SnS and SnSe. Here, we use in situ electron microscopy and diffraction to determine the mechanism and characteristics of ferroelectricity across the SnSe 1-x S x system. We identify two distinct phases of synthetic SnSe 1-x S x : nonpolar (centrosymmetric) equilibrium (α-phase) crystals and metastable crystals adopting a distorted monoclinic structure, which are in-plane ferroelectrics with Curie temperatures of 320 to 420 °C. A surprising structural plasticity of the ferroelectric crystals during heating/cooling indicates a shallow energy landscape. This in turn suggests absence of a pronounced driving force for conversion to the α-phase that can explain the formation of the nonequilibrium crystals and their stability even after transfer to other supports. Our results highlight opportunities for the discovery of novel ferroelectrics among nonequilibrium van der Waals crystals.

Author Correction: Wound healing approach based on excretory-secretory product and lysate of liver flukes

Structure and organization of full-length epidermal growth factor receptor in extracellular vesicles by cryo-electron tomography

We report here transport of full-length epidermal growth factor receptor (EGFR), Insulin Receptor, 7-pass transmembrane receptor Smoothened, and 13-pass Sodium-iodide symporter to extracellular vesicles (EVs) for structural and functional studies. Mass spectrometry confirmed the transported proteins are the most abundant in EV membranes, and the presence of many receptor-interacting proteins in EVs demonstrates their utility for characterizing membrane protein interactomes. Cryo-electron tomography of EGFR-containing EVs reveals that EGFR forms clusters in both the presence and absence of EGF with a ~3 nm gap between the inner membrane and cytoplasmic density. EGFR extracellular region (ECR) dimers do not form regular arrays in these clusters. Subtomogram averaging of the 150 kDa EGF-bound EGFR ECR dimer yielded a 15 Å map into which the crystal structure of the ligand-bound EGFR ECR dimer fits well. These findings refine our understanding of EGFR activation, clustering, and signaling and establish EVs as a versatile platform for structural and functional characterization of human membrane proteins in cell-derived membranes.

The cell-permeable iron chelator M606 inhibits MYCN-driven neuroblastoma via an E2F3-mediated response

Despite Myc oncoproteins being major causal factors in human cancer, they remain “undruggable.” The MYCN oncogene is one of the most powerful prognostic markers for the childhood cancer neuroblastoma and represents an important target for developing novel therapeutics. Here, we report the finding and characterization of M606, a selective small molecule inhibitor of MYCN, which was identified by screening a diverse chemical library. M606 reduced MYCN protein levels in neuroblastoma cell lines and upregulated hypoxia-inducible factor 1 alpha (HIF1A). Using siRNA-mediated knockdown of MYCN , c-Myc , or HIF1A in HepG2 and BE(2)-C cells followed by M606 treatment, we demonstrated that Myc downregulation and HIF1A upregulation were two independent effects of M606 treatment. M606 selectively targeted neuroblastoma cell lines expressing higher levels of MYCN protein and delayed neuroblastoma development in the TH-MYCN transgenic mouse model. Metabolomic analysis showed that M606 modulated glucose metabolism, consistent with a hypoxic response and iron deprivation. Biochemical characterization of M606 not only confirmed its iron-chelating properties but also revealed its ability to downregulate MYCN promoter activity, which could be rescued by the addition of iron. Luciferase assays identified the minimal MYCN promoter region required for the M606 response, which contained overlapping E2F transcription factor binding sites. Further evaluation defined a key role for E2F3 in the M606-mediated response. The finding of a potent cell-permeable iron chelator that can chelate iron to directly downregulate MYCN transcription via an E2F3-mediated response represents a potentially valuable therapeutic approach in the treatment of cancers overexpressing Myc oncoproteins.

Concerted transport and phosphorylation of diacylglycerol at ER–PM contact sites regulate phospholipid dynamics during stress

A universal response of plants to environmental stresses is the activation of plasma membrane (PM) phospholipase C, which hydrolyzes phosphoinositides to produce soluble inositol phosphate and diacylglycerol (DAG). Because of their conical shape, DAG amounts have to be tightly regulated or they can destabilize membranes. We previously showed that upon stress, Synaptotagmin1 (SYT1) transports DAG from the PM to the endoplasmic reticulum (ER) at ER–PM Contact Sites (CS). Here, we addressed the fate of the incoming DAG in the ER. We show that diacylglycerol kinases (DGKs) DGK1 and DGK2 form a module with SYT1 functionally coupling DAG transport and phosphorylation at ER–PM CS. Although SYT1 and DGK1/DGK2 do not show exclusive ER–PM CS localization, their interaction occurs specifically at ER–PM CS and the removal of ER–PM CS abolishes the interaction. Lipidomic analysis of a dgk1dgk2 double mutant supports that DGK1 and DGK2 phosphorylate DAG at the ER and transcriptomic and phenotypic analyses indicate that SYT1 and DGK1/DGK2 are functionally related. Taken together, our results highlight a mechanism at ER–PM CS that coordinates the transfer of DAG from the PM to the ER by SYT1 upon stress and the concomitant phosphorylation of DAG by DGK1 and DGK2 at the ER. These findings underscore the critical role of spatial coordination in lipid metabolism during stress-induced membrane remodeling.

Declining coral calcification to enhance twenty-first-century ocean carbon uptake by gigatonnes

The sensitivity of coral reefs to climate change is well established. As the oceans warm and acidify, the calcification of coral reefs declines with net calcium carbonate dissolution projected under even moderate emissions trajectories. The impact of this on the global carbon cycle is however yet to be accounted for. Here, we use a synthesis of the sensitivity of coral reef calcification to climate change, alongside reef distribution products to estimate alkalinity and dissolved inorganic carbon fluxes resulting from reductions in reef calcification. Using a global ocean biogeochemical model, we simulate the impact on ocean carbon uptake under different emissions scenarios, accounting for uncertainty in present-day calcification rates. Reductions in net coral reef carbonate production can enhance the ocean carbon sink by up to 1.25 GtCO 2 y −1 by midcentury (0.48 GtCO 2 y −1 median estimate) with cumulative ocean carbon uptake up to 13% greater by 2300 (7% median estimate). Our findings indicate that accounting for the coral reef feedback in projections will increase estimates of the remaining carbon budget associated with global warming thresholds, as well as the likelihood that net zero emissions can be achieved without negative emissions.

Pathophysiologically relevant bisphenol S exposure accelerates aging by disrupting brown adipose tissue–regulated energy metabolism

Bisphenol A (BPA) substitutes are widely used as food contact materials and consumer products, while the effects of pathophysiologically relevant concentrations of BPA substitutes on aging remain unclear. In this study, we used Caenorhabditis elegans ( C. elegans ) to investigate the effects of five BPA substitutes [bisphenol S (BPS), bisphenol B, bisphenol F (BPF), tetramethyl BPF, and 4,4′-(Perfluoropropane-2,2-diyl)diphenol] at pathophysiologically relevant exposure levels during aging and examined the underlying mechanisms using a mouse model. Our results indicated that, among the five BPA substitutes, exposure to pathophysiologically relevant concentrations of BPS (300, 450, and 600 nM) accelerated aging in C. elegans . In mice, exposure to a pathophysiologically relevant concentration of BPS (125 μg/kg/day, from 4 to 20 mo of age) similarly reduces the life and health span and accelerates aging phenotypes in multiple tissues. Further investigations demonstrated that long-term BPS exposure resulted in a significantly higher accumulation of BPS in brown adipose tissue (BAT) than in other organs. RNA sequencing analysis of BAT revealed that BPS accelerates BAT aging through multiple pathways. Importantly, transplantation of BAT from BPS-exposed mice into BPS-naive mice accelerated aging in recipients. Conversely, transplantation of BAT from unexposed mice into BPS-exposed mice significantly improved their metabolic status and delayed aging. These findings elucidate the impact of pathophysiologically relevant concentrations of BPS on the aging process and suggest that these effects are likely mediated through the disruption of BAT function.

Structure–function coupling in the first month of life: Associations with age and attention

How brain structure relates to function is a critical and open question in neuroscience. Here, we characterize regional variation in structure–function coupling, capturing the degree to which a cortical region’s structural connections relate to patterns of coordinated neural activity in healthy, term-born neonates ( n = 239). Regional structure–function coupling is heterogeneously patterned across the cortex, with higher coupling in the auditory, lateral prefrontal, and inferior parietal cortices. Average structure–function coupling is negatively associated with age during the first month of life, with age-associated decreases seen in primary sensory systems, specifically in auditory and somatomotor regions. Age-associated “decoupling” of structure and function reflects increasingly segregated patterns of functional connectivity and increasingly integrated patterns of white matter connectivity with age. Notably, higher structure–function coupling after accounting for age in the dorsal attention, cingulo-opercular, and visual systems at birth is associated with faster visuospatial attention to faces at one year of age. These results yield valuable insight into the development of structural and functional connectivity across the cortex, including how interregional variation in structure–function coupling during the first month of life might shape later attention.

Evolutionarily conserved BON1 regulates the basal cytosolic Ca ²⁺ level by calmodulin-independent activation of Ca ²⁺ pumps in <i>Arabidopsis</i>

Plasma membrane-localized autoinhibited Ca 2+ pumps are essential for maintaining basal cytosolic Ca 2+ levels for regulating growth processes and environmental responses. These pumps are known to be activated by calmodulins to maintain Ca 2+ homeostasis in plants and animals. Here, we demonstrate that the evolutionarily conserved copine protein BON1 is critical for maintaining low cytosolic Ca 2+ concentrations by directly regulating two plasma membrane-localized Ca 2+ pumps ACA8 and ACA10 in Arabidopsis . BON1 interacts with a region within the N-terminal domain of ACA8 and ACA10, preceding the calmodulin binding sites, and stimulates ACA8 activity. This activation can occur without calmodulin binding, indicating that BON1 and calmodulin independently regulate the Ca 2+ pump. Loss of BON1 function results in elevated basal cytosolic Ca 2+ concentrations, which can be partially rescued by overexpressing hyperactive ACA8 or ACA10. Furthermore, we show that BON1 has one high-affinity Ca 2+ binding site in the VWA domain that is critical for activation of ACA8 as well as for BON1 function, suggesting a feedback mechanism for Ca 2+ homeostasis at resting concentrations. Our findings suggest that this Ca 2+ responsive regulatory mechanism extends beyond Arabidopsis , as we show interactions between ACA and BON proteins from algae to flowering plants, pointing to an ancient regulatory mechanism for maintaining low basal cytosolic Ca 2+ . Notably, a human plasma membrane-localized autoinhibited Ca 2+ pump can also be activated by a human BON protein in a yeast functional assay system, suggesting evolutionary conservation in Ca 2+ regulation across species.

Circuit complexity and functionality: A statistical thermodynamics perspective

Circuit complexity, defined as the minimum circuit size required for implementing a particular Boolean computation, is a foundational concept in computer science. Determining circuit complexity is believed to be a hard computational problem. Recently, in the context of black holes, circuit complexity has been promoted to a physical property, wherein the growth of complexity is reflected in the time evolution of the Einstein-Rosen bridge (“wormhole”) connecting the two sides of an anti-de Sitter “eternal” black hole. Here, we are motivated by an independent set of considerations and explore links between complexity and thermodynamics for functionally equivalent circuits, making the physics-inspired approach relevant to real computational problems, for which functionality is the key element of interest. In particular, our thermodynamic framework provides an alternative perspective on the obfuscation of programs of arbitrary length—an important problem in cryptography—as thermalization through recursive mixing of neighboring sections of a circuit, which can be viewed as the mixing of two containers with “gases of gates.” This recursive process equilibrates the average complexity and leads to the saturation of the circuit entropy, while preserving functionality of the overall circuit. The thermodynamic arguments hinge on ergodicity in the space of circuits which we conjecture is limited to disconnected ergodic sectors due to fragmentation. The notion of fragmentation has important implications for the problem of circuit obfuscation as it implies that there are circuits of same size and functionality that cannot be connected via a polynomial number of local moves. Furthermore, we argue that fragmentation is unavoidable unless the complexity classes NP and coNP coincide, a statement that implies the collapse of the polynomial hierarchy of computational complexity theory to its first level.

A mouse model of Jansen’s metaphyseal chondrodysplasia for investigating disease mechanisms and candidate therapeutics

Jansen’s metaphyseal chondrodysplasia (JMC) is a rare disorder caused by activating mutations in the parathyroid hormone (PTH)/PTH-related peptide (PTHrP) receptor (PTH1R). Patients exhibit short stature, dysmorphic bones, and severe growth plate abnormalities, as well as hypercalcemia, hypercalciuria, hypophosphatemia, and reduced plasma PTH levels. Humanized PTH1R (hPTH1R) mice expressing the H223R-hPTH1R JMC mutation die early without breeding. We therefore generated and characterized a stable mouse line expressing the T410R-hPTH1R allele, which confers a milder disease phenotype in patients. Mutant mice show near-normal longevity and reproductive capacity yet exhibit a profound skeletal phenotype characteristic of the disease. The long bones of T410R mice are markedly misshapen and have expanded metaphyses with disarrayed chondrocyte zones in growth plates and reduced primary spongiosa. PET/CT scanning revealed diminished uptake of [ 18 F]-sodium fluoride in the growth plate area, consistent with reduced mineralization and vascularization. Genetic ablation of Hdac4 rescued the growth plate abnormalities in T410R mice, thereby establishing the PTH1R-Gαs-cAMP-PKA-SIK3-HDAC4/5 pathway as the main mediator of growth plate abnormalities in JMC. Serum calcium was elevated and endogenous PTH was suppressed in T410R mice, and both parameters could be normalized by acute injection of an optimized PTH inverse agonist peptide. The T410R mouse thus represents a stable animal model of JMC that recapitulates the abnormalities in skeletal development and mineral ion homeostasis which characterize this disease. The mice should help efforts to further define the cellular and molecular mechanisms underlying the JMC phenotype and to develop a potential mode of therapy.