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Biology subjects

Carroll, T. J.

Publications and source records attributed to Carroll, T. J..

At least 19 recordsLinked to original sources

Transient architecture of the embryonic pancreas determines endocrine mass

During organogenesis, epithelial tissues undergo extensive three-dimensional (3D) remodeling while simultaneously generating specialized cell types. Whether these transient architectural states actively instruct lineage allocation remains unclear. Here we identify a morphogenetic stage in which resolution of epithelial stratification is required for lineage allocation and establishment of endocrine cell mass. We show that loss of the Hippo pathway regulator Merlin disrupts lumen morphogenesis and prevents formation of the transient 3D epithelial architecture that characterizes normal pancreas development. Failure to establish this architectural state alters lineage allocation, impairing acinar differentiation, markedly reducing adult endocrine cell mass, and disrupting glucose homeostasis. Mosaic analyses reveal that these lineage defects arise non-cell autonomously, demonstrating that epithelial architecture itself instructs cell fate decisions. Mechanistically, Merlin coordinates PI3K-regulated polarized membrane trafficking required for apical membrane biogenesis and lumen formation. Together, these findings identify Merlin-dependent membrane trafficking as a mechanism coupling epithelial morphogenesis to lineage allocation and demonstrate that transient developmental architectures can determine the cellular composition of mature organs.

developmental biology↗

SPATIALLY PATTERNED PODOCYTE STATE TRANSITIONS COORDINATE AGING OF THE GLOMERULUS

BackgroundWith the US population living longer, the risk, incidence, prevalence and severity for chronic kidney diseases become more abundant. Glomerular diseases are the leading cause for chronic and end-stage kidney disease. Yet, the cellular responses and the underlying mechanisms of progressive glomerular disease, which ultimately leads to glomerulosclerosis and loss of kidney function with advancing age, are poorly understood. MethodsKidneys of young (4 months-old), middle-aged (20 months-old) and aged (24 months-old) mice were separated into outer cortex and juxta-medullary region and processed for single nuclei transcriptomics. Focusing on the aging glomerulus data were analyzed using a state-of-the-art analysis pipeline dissecting out the cellular age- and kidney region-specific responses. ResultsGlobal analysis of the transcriptome reveals regional-specific differences that are detectable across multiple cell types exemplified by the expression of Napsa as a bona-fide juxta-medullary marker. In contrast aging led to rather cell type-specific responses. In the glomerulus, healthy podocytes were characterized by expression of canonical podocyte genes; conversely the senescent, aged podocytes were characterized by the down-regulation of canonical podocyte genes and the emergence of inflammatory and senescent signatures. Interestingly, these senescent podocytes were primarily located in the juxtamedullary region suggesting that juxtamedullary podocytes are more sensitive. Yet, instead of aging being defined by distinct cell states, the profiles, as well as ligand-receptor and pseudotime analyses suggest that podocytes aging is selective and coordinated, not universal degeneration. This was different to the other glomerular cell types, parietal epithelial cells, glomerular endothelial cells and mesangial cells. While they also as existed in different subpopulations, they exhibited little regional-, or age-depended changes. Finally proximal tubular aging manifested itself as discrete cellular states. ConclusionsThe single nuclei transcriptomics of the aging kidney provides a mechanistic explanation for regional susceptibility of nephrons and suggests that the future therapeutic strategies need to consider the cellular and spatial complexity of the glomerulus.

bioinformatics↗

Subcortical control of reaching in humans

Accurate visually guided reaching requires transformation of target-related photoreceptor responses into precisely coordinated activation of trunk and arm muscles. The cerebral cortex is widely believed to compute the requisite kinematic and musculoskeletal dynamics strategies in humans 1-3, even though vertebrates lacking a cerebral cortex achieve sophisticated visuomotor control 4-6, and brainstem circuits executing coordinated eye and head gaze shifts perform analogous sensorimotor computations in non-human primates 7. Here we used a visuomotor reaching task that yields extremely rapid, "express", target-directed muscle activations 8-10 to test whether a putative subcortical sensorimotor network can compute musculoskeletal dynamics to initiate reaching in humans. We found coordinated express visuomotor responses (EVRs) in task-relevant shoulder, elbow, and bi-articular muscles that reflected both starting posture and target direction in similar patterns to longer latency, presumably cortically mediated, muscle responses. When the task goal was to reach away from the stimulus (i.e. an "anti-reach"; 11) the EVR involved coordinated muscle activation to initiate the hand toward the stimulus location, opposite to the subsequent goal-directed response. The results suggest a unified theory of visuomotor control for reaching and gaze shifts, in which subcortical systems compute musculoskeletal dynamics based on sensory target information and cortically derived context. The results imply that the transformation from motor goals in extrapersonal space into musculoskeletal dynamics can be performed by neural circuitry in humans that does not involve the sensorimotor cortex.

neuroscience↗

Mitochondrial organization in the developing proximal tubule is controlled by LRRK2

The proximal tubule of the nephron resorbs water, amino acids and glucose, and its energy demands are high. Formation of the cellular machinery for energy production is an essential step in proximal tubule epithelial cell (PTC) differentiation, and this report focuses on how mitochondria in nascent PTCs are redistributed from their initial apical position to their ultimate basolateral location. We found that mitochondria move from the apical to basolateral side of the PTC coincident with the initiation of lumen flow and that proximal tubules deficient in filtration (aglomerular mice and kidney organoids) maintain their mitochondria in the apical position, indicating that flow is necessary and sufficient for localization. Further, we show that mitochondrial localization depends on the activity of LRRK2 in vitro and in vivo. Modeling the effect of fluid flow on PTCs demonstrates that LRRK2 activity is regulated by fluid shear stress, providing an explanation for how onset of flow in the newly differentiated proximal tubule may trigger the apical-to-basolateral dissemination of mitochondria that forms the template for subsequent PTC maturation. Our findings indicate that mitochondrial redistribution is one component of a cellular program in the nascent PTC that drives function and that this process is regulated by flow.

developmental biology↗

Benefits of dual-tasking on implicit sensorimotor adaptation

Attention plays a crucial role in maintaining precision and effectiveness in goal-directed actions. Although there is evidence that dividing attention across tasks impairs performance in various domains, the impact of attention on sensorimotor adaptation remains inconclusive, with some studies reporting deficits and others showing no effects. Because sensorimotor adaptation arises from the interaction of explicit and implicit processes, this discrepancy may reflect differential effects of attention on each process. Here, we investigate how divided attention influences implicit sensorimotor adaptation using an error-clamp paradigm, coupled with a random dot kinematogram (RDK) motion coherence discrimination task. We also assessed whether the timing of the secondary task affects error processing during sensorimotor adaptation by presenting the RDK either during the outward movement (coinciding with error feedback), or the inward movement (following error feedback). We observed that attentional manipulation influenced implicit sensorimotor adaptation only when the RDK was presented on the outward movement, not the inward movement. Remarkably, implicit sensorimotor adaptation was enhanced when attention was divided, compared to when attention was focused entirely on the adaptation task. This suggests that implicit sensorimotor adaptation is sensitive to attentional demand, particularly during the time window where error feedback is received.

neuroscience↗

Defects in nephrogenesis result in an expansion of the Foxd1+ stromal progenitor population

Reciprocal signaling interactions coordinate multiple aspects of kidney development. While signals from the stroma have been shown to regulate nephron progenitor cell (NPC) differentiation, much less is known about regulation of the stromal progenitor population. Here, we demonstrate that disruption of the NPC lineage via loss of Wt1 (i.e., Six2cre;Wt1c/c) results in an expansion of Foxd1+ stromal progenitor cells. Analyses of the developing stroma in two additional models, including Wnt4-null mutants (which fail to form nephron structures similar to Six2cre;Wt1c/c kidneys) and NPC ablation via diphtheria toxin (i.e., Six2cre;RosaDTAc/+), both phenocopy Six2cre;Wt1c/c mutants, thus further confirming that defects in the NPC lineage result in abnormal development of the stromal progenitor population. Furthermore, we identify a subcluster of the Foxd1+ stroma that appears expanded in the three mutant mouse models and conserved in human fetal kidneys. Overall, the findings from this study suggest that loss of differentiating nephron structures may result in possible over proliferation of the stromal progenitor population and/or a block in stromal differentiation and further highlight how crosstalk amongst the progenitor cell lineages coordinates multiple aspects of kidney development. KEY POINTSO_LIMutant mouse models targeting the nephron lineage (i.e., Six2cre;Wt1c/c and Wnt4-null mutants which fail to form early nephron structures) suggest that a block in NPC differentiation results in an abnormal expansion of the Foxd1+ stromal progenitor population. C_LIO_LIMutant kidneys with NPC ablation (i.e., Six2cre;RosaDTAc/+) show maintenance of stromal progenitors independent of signals from adjacent nephron progenitors and ureteric bud. C_LIO_LISingle nuclei RNA-seq identifies three subclusters of the Foxd1+ stromal progenitor population at E15.5, including one cluster of proliferating cells and a distinct Fap+, Igf1+, Gria1+, Gdnf- subcluster which appears expanded in Six2cre;Wt1c/c, Wnt4-null, and Six2cre;RosaDTAc/+ mutant kidneys and conserved in human fetal kidneys. C_LI

developmental biology↗

Zonal endothelial cell heterogeneity underlies murine renal vascular development.

The renal vasculature consists of highly specialized blood vessels that carry out distinct physiological functions. Defining their transcriptional signatures and tracing their developmental ontogeny has thus far been challenging due to a lack of regionally specific endothelial biomarkers. Here, we performed single nuclear RNA sequencing (snucRNA-Seq) to interrogate embryonic renal endothelial cells. We identified nine different endothelial cell types, and validated expression of novel candidates using multiplex RNAScope. We interrogate biological characteristics, including cell cycle stage, of developmental blood vessels with a variety of in vivo tools. Using genetic tools based on expression of tip cell marker Esm1, we performed detailed lineage tracing, demonstrating multi-clonal and multi-directional endothelial contribution to glomerular vasculature. Together, this study provides the first validated, tool-focused developmental atlas of the murine renal vasculature and elucidates several novel cellular mechanisms of nephron vascularization.

developmental biology↗

Integration of spatial and single nucleus transcriptomics to map gene expression in the developing mouse kidney

The kidney is a complex organ requiring tightly coordinated interactions between epithelial, endothelial, and mesenchymal cells during development. Congenital kidney defects can result in kidney disease and renal failure, highlighting the importance of understanding kidney formation mechanisms. Advances in RNA sequencing have revealed remarkable cellular heterogeneity, especially in the kidney stroma, though relationships between stromal, epithelial, and endothelial cells remain unclear. This study presents a comprehensive gene expression atlas of embryonic and postnatal kidneys, integrating single-nucleus and in situ RNA sequencing data. We developed the Kidney Spatial Transcriptome Analysis Tool (KSTAT), enabling researchers to identify cell locations, predict cell-cell communication, and map gene pathway activity. KSTAT revealed significant heterogeneity among embryonic kidney pericytes, providing a critical resource for hypothesis generation and advancing knowledge of kidney development and disease.

developmental biology↗

Dopamine alters motor learning performance in the presence and absence of feedback

We often choose to learn motor skills not only because of some external reward, but also because motor learning, in and of itself, is satisfying. While dopamine is thought to drive reward-based motor learning, it remains unclear whether dopamine is implicated in motor learning under conditions ostensibly driven by intrinsic rewards/motivation (i.e., in the absence of extrinsic feedback or reward). Here, by pharmacologically manipulating dopamine using the dopamine precursor Levodopa, we investigated the role of dopamine in an explicit motor learning task guided by internally determined signals of performance success, by removing intrinsic feedback about task success. Specifically, we asked participants to strategically aim away from presented targets by various instructed angles: a form of explicit motor learning that contributes to performance in the classic visuomotor rotation task. In the feedback condition, targets jumped mid-movement by the instructed angle, such that success in target hitting depended on successfully aiming away by the instructed angle. In the no-feedback condition, intrinsic feedback about task success was removed by having targets disappear mid-movement, such that participants could not know if they succeeded at hitting the targets or not. We found that dopamine altered performance, both with and without task feedback about task success. This provides direct evidence for a role of dopamine in motor learning driven by internal task goals.

neuroscience↗

Time affects a time-consuming, flexible component and a fast, inflexible component of sensorimotor adaptation.

Prior learning can impair future learning when the requirements of the two memories conflict, a phenomenon termed anterograde interference. In sensorimotor adaptation, the passage of time between initial and future learning can reduce such interference effects. However, we still do not fully understand how time affects learning, as some studies found no effects of time on interference. One possible explanation for such inconclusive findings is that time affects distinct processes underpinning sensorimotor adaptation differently, and these processes may compensate for each others effects on behaviour. Here, we used task manipulations that (1) dissociate adaptation processes driven by task errors from adaptation processes driven by sensory prediction errors, and (2) separate the task-error driven adaptation processes into a flexible component that could not be acquired under time-pressure, or a less-flexible component that could not be acquired under time-pressure. The time between initial and subsequent learning seemed to alter both the flexible and inflexible components of adaptation driven by task errors. Time also led to a small reduction of interference arising from sensory prediction errors. Thus, we provide evidence that multiple components of sensorimotor adaptation are sensitive to the passage of time.

neuroscience↗

Epithelial tubule interconnection driven by HGF-Met signaling in the kidney

The formation of functional epithelial tubules is a central feature of many organ systems. Although the process of tubule formation by epithelial cells is well-studied, the way in which tubules connect with each other (i.e. anastomose) to form functional networks both in vivo and in vitro is not well understood. A key, unanswered question in the kidney is how the renal vesicles of the embryonic kidney connect with the nascent collecting ducts to form a continuous urinary system. We performed a ligand-receptor pair analysis on single cell RNA-seq data from embryonic mouse kidney tubules undergoing anastomosis to select candidates that might mediate this process in vivo. This analysis identified hepatocyte growth factor (HGF), which has known roles in cell proliferation, migration, and tubulogenesis, as one of several possible candidates. To test this possibility, we designed a novel assay to quantitatively examine epithelial tubule anastomosis in vitro using epithelial spheroids with fluorescently-tagged apical surfaces to enable direct visualization of anastomosis. This revealed that HGF is a potent inducer of tubule anastomosis. Tubule anastomosis occurs through a proliferation-independent mechanism that acts through the MAPK signaling cascade and matrix metalloproteinases (MMPs), the latter suggestive of a role in extracellular matrix turnover. Accordingly, treatment of explanted embryonic mouse kidneys with HGF and collagenase was sufficient to induce kidney tubule anastomosis. These results lay the groundwork for investigating how to promote functional interconnections between tubular epithelia, which have important clinical implications for utilizing in vitro grown kidney tissue in transplant medicine.

developmental biology↗

Cycling Cadence Selections at Different Saddle Heights Minimize Muscle Activation Rather Than Energy Cost

Unlike walking and running, people do not consistently choose cadences that minimize energy consumption when cycling. Assuming a common objective function for all forms of locomotion, this suggests either that the neural control system relies on indirect sensorimotor cues to energetic cost that are approximately accurate during walking but not cycling, or that an alternative objective function applies that correlates with energy expenditure in walking but not cycling. This study compared how objective functions derived as proxies to 1) energy cost or 2) an avoidance of muscle fatigue predicted self-selected cycling cadences (SSC) at different saddle heights. Saddle height systematically affected SSC, with lower saddles increasing SSC and higher saddles decreasing SSC. Both fatigue-avoidance and energy-expenditure cost functions derived from muscle activation measurements showed minima that closely approximated the SSCs. By contrast, metabolic power derived from VO2 uptake was minimal at cadences well below the SSC across all saddle height variations. The mismatch between the cadence versus muscle activation and the cadence versus metabolic energy relations is likely due to additional energy costs associated with performing mechanical work at higher cadences. The results suggest that the nervous system places greater emphasis on muscle activation than on energy consumption for action selections in cycling.

evolutionary biology↗

Action history and target uncertainty co-determine human reaching direction under time pressure

Given the inaccuracies that are inherent in biological sensory and motor functions, animal sensorimotor control should be probabilistic. Effective neural control systems for movement must estimate the most likely true state of the world on the basis of uncertain sensory information, and to select and execute movements that are most likely to be successful given motor variability. Bayesian inference dictates that if sensory information is ambiguous (e.g. low light conditions), animals should rely more on their past experience of target locations to guide motor planning, and less on their current sensory information about target location. Here we investigated how time pressure affects degree to which the precision of sensory information about a target influences movement direction bias towards previous target locations. We used a paradigm developed by Dekleva et al. (2016) that involved uncertain cues to the location of a hidden target for reaching with movement preparation time strictly controlled. One group of participants (n=10) were required to initiate their reaches within 150-300ms of target presentation, and a second group (n=10) were required to initiate their reaches with 1150-1300ms of target presentation. We found that participants relied more on prior target location information when target precision was reduced under time pressure, which suggests that integration of target uncertainty information according to Bayesian principles is an inherent component of sensorimotor transformation and does not require time-consuming cognitive processes.

neuroscience↗

Enhanced neural representation of reach target direction for high reward magnitude but not high target probability.

Many characteristics of goal-directed movements, such as their initiation time, initial direction, and speed, are influenced both by the details of previously executed movements (i.e. action history), and by the degree to which previous movements were rewarded or punished (i.e. reward history). In reinforcement learning terms, when movements are externally cued, action and reward history jointly define the probability and magnitude of positive/negative outcomes of available options, and therefore their pre-stimulus expected value. To dissociate which of these neurocomputational variables influence sensorimotor brain processing, we studied how reach behaviour and evoked brain responses are affected by independent manipulations of action and reward history. We found that movements were initiated earlier both for more frequently repeated targets and targets associated with higher reward magnitude, but only movements to highly rewarded targets had higher movement speeds. Classical visually-evoked encephalographic (EEG) potentials (P1/N1) were not affected by either reward magnitude or target probability. There were, however, amplified midline ERP responses at centroparietal electrodes for rewarded targets and movements compared to control, but no differences between more frequently presented targets and control. Critically, the spatial precision of decoded target locations extracted from a multivariate linear decoding model of EEG data was greater for target locations associated with higher reward magnitude than for control target locations ([~]150-300ms after target presentation). Again, there were no differences in the precision of decoded target direction representations between more frequent target locations and control target locations. These data suggest that the expected reward magnitude associated with an action, rather than its long-run expected value, determines the precision of early sensorimotor processing. Significance StatementWe move more quickly and more accurately toward goals that we value more highly, and this is due partly to enhanced motor preparation. However, our expectations about the value of an action depend both on the probability of its requirement and the magnitude of the reward associated with it. Here we disentangled the influence of reward magnitude and probability on early sensorimotor processing via a multivariate linear decoding approach to extract target direction from scalp encephalograms. We found that the spatial precision of decoded target direction was greater for high reward targets but not for more probable targets. Thus, early sensorimotor processing is sharpened when the magnitude of reward associated with movement to a cued target is high. HighlightsO_LIThe direction of movement can be reliably decoded from the scalp EEG from [~]80ms after target presentation. C_LIO_LIThe neural representation of movement direction is more precise for targets that are associated with high reward, but not for targets that are more probable. C_LIO_LIThe magnitude of reward associated with movement to a presented target, rather than the long-run expected value of the movement, sharpens the spatial precision of early sensorimotor processing. C_LI

neuroscience↗

Increased force and elastic energy storage are not the mechanisms that improve jump performance with accentuated eccentric loading during a constrained vertical jump

ObjectiveAccentuated eccentric loading (AEL) involves higher load applied during the eccentric phase of a stretch-shortening cycle movement, followed by a sudden removal of load before the concentric phase. Previous studies suggest that AEL enhances human countermovement jump performance, however the mechanism is not fully understood. Here we explore whether isolating additional load during the countermovement is sufficient to increase ground reaction force, and hence elastic energy stored, at the start of the upward movement and whether this leads to increased jump height or power generation. MethodsWe conducted a trunk-constrained vertical jump test on a custom-built device to isolate the effect of additional load while controlling for effects of squat depth, arm swing, and coordination. Twelve healthy, recreationally active adults (7 males, 5 females) performed maximal jumps without AEL, followed by randomised AEL conditions prescribed as a percentage of body mass (10%, 20%, and 30%), before repeating jumps without AEL. Results. No significant changes in vertical ground reaction force at the turning point were observed. High load AEL conditions (20% and 30% body weight) led to slight reductions in jump height, primarily due to decreased hip joint and centre of mass work. AEL conditions did not alter peak or integrated activation levels of the knee extensor muscles. ConclusionThese findings suggest that increased elastic energy return may not be the primary mechanism behind the potentiating effects of AEL on jump performance, and other factors such as rate of descent, squat depth, or body configuration may contribute to effective AEL.

biophysics↗

An in-silico investigation of the effect of changing cycling crank power and cadence on muscle energetics and active muscle volume

This study used musculoskeletal modelling to explore the relationship between cycling conditions (power output and cadence) and muscle activation and metabolic power. We hypothesized that the cadence that minimized the simulated average active muscle volume would be higher than that which minimized the simulated metabolic power. We validated the simulation by comparing predicted muscle activation and fascicle velocities from select muscles with experimental records of electromyography and ultrasound images. We found strong correlations for averaged muscle activations and moderate to good correlations for fascicle dynamics. These correlations tended to weaken when analyzed at the individual participant level. Our study revealed a curvilinear relationship between average active muscle volume and cadence, with the minimum active volume being aligned to the self-selected cadence. The simulated metabolic power was consistent with previous results and was minimized at lower cadences than that which minimized active muscle volume across power outputs. Whilst there are some limitations to the musculoskeletal modelling approach, the findings suggest that minimizing active muscle volume may be a more important factor than minimizing metabolic power for self-selected cycling cadence preferences. Further research is warranted to explore the potential of an active muscle volume based objective function for control schemes across a wider range of cycling conditions.

bioengineering↗

Genetically engineering endothelial niche in human kidney organoids enables multilineage maturation, vascularization, and de novo cell types

Vascularization plays a critical role in organ maturation and cell type development. Drug discovery, organ mimicry, and ultimately transplantation in a clinical setting thereby hinges on achieving robust vascularization of in vitro engineered organs. Here, focusing on human kidney organoids, we overcome this hurdle by combining an inducible ETS translocation variant 2 (ETV2) human induced pluripotent stem cell (iPSC) line, which directs endothelial fate, with a non-transgenic iPSC line in suspension organoid culture. The resulting human kidney organoids show extensive vascularization by endothelial cells with an identity most closely related to endogenous kidney endothelia. Vascularized organoids also show increased maturation of nephron structures including more mature podocytes with improved marker expression, foot process interdigitation, an associated fenestrated endothelium, and the presence of renin+ cells. The creation of an engineered vascular niche capable of improving kidney organoid maturation and cell type complexity is a significant step forward in the path to clinical translation. Furthermore, this approach is orthogonal to native tissue differentiation paths, hence readily adaptable to other organoid systems and thus has the potential for a broad impact on basic and translational organoid studies. Translational StatementDeveloping therapies for patients with kidney diseases relies on a morphologically and physiologically representative in vitro model. Human kidney organoids are an attractive model to recapitulate kidney physiology, however, they are limited by the absence of a vascular network and mature cell populations. In this work, we have generated a genetically inducible endothelial niche that, when combined with an established kidney organoid protocol, induces the maturation of a robust endothelial cell network, induces a more mature podocyte population, and induces the emergence a functional renin population. This advance significantly increases the clinical relevance of human kidney organoids for etiological studies of kidney disease and future regenerative medicine strategies. Graphical AbstractGenetically engineered endothelial niche induces mature cell populations in human kidney organoids O_FIG O_LINKSMALLFIG WIDTH=200 HEIGHT=100 SRC="FIGDIR/small/542848v1_ufig1.gif" ALT="Figure 1"> View larger version (35K): org.highwire.dtl.DTLVardef@1b129d4org.highwire.dtl.DTLVardef@313ae3org.highwire.dtl.DTLVardef@111c91org.highwire.dtl.DTLVardef@16a8d45_HPS_FORMAT_FIGEXP M_FIG C_FIG

bioengineering↗

Stromal netrin-1 coordinates renal arteriogenesis and mural cell differentiation

The kidney vasculature has a uniquely complex architecture that is essential to proper renal function. Little is known about the molecular mechanisms that direct where and when blood vessels form during kidney development. We identified a regionally-restricted, stroma-derived signaling molecule, netrin-1 (Ntn1), as a putative regulator of vascular patterning. We generated a stromal progenitor-specific knockout of netrin-1 (Ntn1SPKO) that resulted in smaller postnatal kidneys with altered epithelial development and profound defects in arterial and capillary architecture. We also found significant loss of arterial vascular smooth muscle cell (vSMC) coverage and ectopic smooth muscle cell deposition at the kidney cortex. Transcriptomic analysis of Ntn1SPKO kidneys revealed downregulation of Klf4, which we find expressed in stromal progenitors. Deletion of Klf4 in the stroma largely phenocopies loss of Ntn1, and expression of Klf4 in Ntn1SPKO kidneys rescues ectopic vSMC deposition. Vascular defects observed in Ntn1SPKO are transient, as both arterial and smooth muscle coverage defects resolve late in development, however ectopic peripheral smooth muscle perdures perinatally. These data suggest a stromal-intrinsic Ntn1-Klf4 axis acting as an essential mediator of stromal crosstalk and vascular progenitor differentiation.

developmental biology↗