Precise spatial restriction of BMP signaling in developing joints is perturbed upon loss of embryo movement

Singh, Pratik; Shea, Claire A.; Sonker, Shashank Kumar; Rolfe, Rebecca A.; Ray, Ayan; Kumar, Sandeep; Gupta, Pankaj; Murphy, Paula; Bandyopadhyay, Amitabha

doi:10.1242/dev.153460

Cited by 36 publications

(61 citation statements)

References 43 publications

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“…Another striking aspect of the pattern is territories of reduced YAP in the sub‐chondral zone, proximal and distal to the shoulder and elbow joint. We have previously shown that territories of Wnt and BMP signalling are distinct and complimentary at rudiment termini with Wnt active in the joint and BMP in the sub‐chondral region and that this spatial organization of distinct signalling territories is lost under immobilization in both chick and mouse models . Here we show that distinct territories of YAP accumulation are also homogenized in the absence of movement.…”

Section: Discussionsupporting

confidence: 52%

“…We have previously used a comparative transcriptomics approach to show extensive alteration of gene expression in immobilized developing humeri and associated joints: Genes associated with Wnt signalling and other regulatory pathways were among the most sensitive to immobilization . We recently showed that Wnt and BMP signalling pathways are reciprocally regulated at the joint interface in response to movement . However, precisely how cells transduce physical stimuli to impact gene expression remains unknown.…”

Section: Introductionmentioning

confidence: 99%

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Localization of YAP activity in developing skeletal rudiments is responsive to mechanical stimulation

Shea

Rolfe

McNeill

et al. 2019

Developmental Dynamics

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Background Normal skeletal development, in particular ossification, joint formation and shape features of condyles, depends on appropriate mechanical input from embryonic movement but it is unknown how such physical stimuli are transduced to alter gene regulation. Hippo/Yes‐Associated Protein (YAP) signalling has been shown to respond to the physical environment of the cell and here we specifically investigate the YAP effector of the pathway as a potential mechanoresponsive mediator in the developing limb skeleton. Results We show spatial localization of YAP protein and of pathway target gene expression within developing skeletal rudiments where predicted biophysical stimuli patterns and shape are affected in immobilization models, coincident with the period of sensitivity to movement, but not coincident with the expression of the Hippo receptor Fat4. Furthermore, we show that under reduced mechanical stimulation, in immobile, muscle‐less mouse embryos, this spatial localization is lost. In culture blocking YAP reduces chondrogenesis but the effect differs depending on the timing and/or level of YAP reduction. Conclusions These findings implicate YAP signalling, independent of Fat4, in the transduction of mechanical signals during key stages of skeletal patterning in the developing limb, in particular endochondral ossification and shape emergence, as well as patterning of tissues at the developing synovial joint.

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Section: Discussionsupporting

confidence: 52%

Section: Introductionmentioning

confidence: 99%

Localization of YAP activity in developing skeletal rudiments is responsive to mechanical stimulation

Shea

Rolfe

McNeill

et al. 2019

Developmental Dynamics

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“…A further possibility for why some joint shapes were more abnormal in the reduced muscle group than in the muscleless group could be due to secretion of factors from the muscle (which would impact only on the reduced‐muscle group and not the muscleless group). Bone‐muscle crosstalk has been shown to be important for both bone and muscle (reviewed in Brotto and Bonewald) and it is possible that similar processes play a role in early cartilage development and cartilage morphogenesis …”

Section: Discussionmentioning

confidence: 99%

“…Fetal movements are important for the development of healthy joints and absent or abnormal fetal movements can lead to developmental skeletal abnormalities such as developmental dysplasia of the hip (DDH) and arthrogryposis . DDH is a condition in which the immature hip joint is unstable or dislocated, with an incidence of 1.3 per 1,000 live births .…”

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confidence: 99%

“…While the very early stages of joint development occur independently of fetal movements, 10,11 numerous animal studies have described the importance of movement for morphogenesis and cavitation of the joint. 2,[12][13][14] The most commonly used model systems are pharmacologically immobilized chick and zebrafish embryos, zebrafish mutants and genetically modified mouse lines in which skeletal muscle is reduced, absent or abnormal. [15][16][17][18][19] Immobilized joints of developing chicks and mice fail to undergo cavitation, 2,3,10,13,15 while a range of shape effects have been reported in zebrafish, chicks and mice including simpler, smaller or malformed articular surfaces with absent or reduced muscle attachment sites.…”

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confidence: 99%

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Effects of Abnormal Muscle Forces on Prenatal Joint Morphogenesis in Mice

Sotiriou

Rolfe

Murphy

et al. 2019

Journal Orthopaedic Research

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Fetal movements are essential for normal development of the human skeleton. When fetal movements are reduced or restricted, infants are at higher risk of developmental dysplasia of the hip and arthrogryposis (multiple joint contractures). Joint shape abnormalities have been reported in mouse models with abnormal or absent musculature, but the effects on joint shape in such models have not been quantified or characterized in detail. In this study, embryonic mouse forelimbs and hindlimbs at a single developmental stage (Theiler Stage 23) with normal, reduced, or absent muscle were imaged in three‐dimensions. Skeletal rudiments were virtually segmented and rigid image registration was used to reliably align rudiments with each other, enabling repeatable assessment and measurement of joint shape differences between normal, reduced‐muscle and absent‐muscle groups. We demonstrate qualitatively and quantitatively that joint shapes are differentially affected by a lack of, or reduction in, skeletal muscle, with the elbow joint being the most affected of the major limb joints. Surprisingly, the effects of reduced muscle were often more pronounced than those of absent skeletal muscle, indicating a complex relationship between muscle mass and joint morphogenesis. These findings have relevance for human developmental disorders of the skeleton in which abnormal fetal movements are implicated, particularly developmental dysplasia of the hip and arthrogryposis. © 2019 Orthopaedic Research Society. Published by Wiley Periodicals, Inc. J Orthop Res 37:2287–2296, 2019

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Systemic versus local patterns of limb joint articular morphology inferred from relative distances from morphological centroid

Horbaly,

Hubbe

2024

The Anatomical Record

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Joint morphogenesis is a complex process known to require the interaction of developmental cascades and mechanical loading, yet many details of this interaction are incompletely understood. While prior work has established populational patterns of joint morphological (co)variance, exploring how these patterns manifest within the individual provides information on the deployment of morphogenic processes as either systemic or local influences on joint shape. To better identify the patterns of variance‐generating morphogenic processes, this study investigates the degree to which individual joint shapes deviate from population averages systematically across the body. Using three‐dimensional landmark data from 200 adult skeletons, we ranked individuals based on their distances from morphological centroids for eight major joints. Spearman correlations assessed associations between ranks across various articular pairings, testing hypotheses regarding systemic versus localized variance. Results reveal low coordination between deviations observed in conarticular surfaces, functional analogs, and same‐bone surfaces; however strong associations exist between antimeres, suggesting the left–right deployment of variance‐generating morphogenic patterns is highly consistent. These results support a model of localized rather than systemic processes driving variation in joint shape. While more remains to be elucidated about the specifics of articular surface morphogenesis, these findings advance our understanding of the systems of variance generation at play during development and growth of our definitive joint morphology.

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Precise spatial restriction of BMP signaling in developing joints is perturbed upon loss of embryo movement

Cited by 36 publications

References 43 publications

Localization of YAP activity in developing skeletal rudiments is responsive to mechanical stimulation

Localization of YAP activity in developing skeletal rudiments is responsive to mechanical stimulation

Effects of Abnormal Muscle Forces on Prenatal Joint Morphogenesis in Mice

Systemic versus local patterns of limb joint articular morphology inferred from relative distances from morphological centroid

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