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Effects of Myostatin on Nuclear Morphology at the Myotendinous Junction

Amemiya, Hikari; Yamamoto, Masahito; Higa, Kazunari; Watanabe, Genji; Taniguchi, Shuichiro; Kitamura, Kei; Jeong, Juhee; Yanagisawa, Nobuaki; Fukuda, Ken-Ichi; Abe, Shinichi
Myostatin (Myo) is known to suppress skeletal muscle growth, and was recently reported to control tendon homeostasis. The purpose of the present study was to investigate the regulatory involvement of Myo in the myotendinous junction (MTJ) in vivo and in vitro. After Achilles tendon injury in mice, we identified unexpected cell accumulation on the tendon side of the MTJ. At postoperative day 7 (POD7), the nuclei had an egg-like profile, whereas at POD28 they were spindle-shaped. The aspect ratio of nuclei on the tendon side of the MTJ differed significantly between POD7 and POD28 (p = 4.67 × 10-34). We then investigated Myo expression in the injured Achilles tendon. At the MTJ, Myo expression was significantly increased at POD28 relative to POD7 (p = 0.0309). To investigate the action of Myo in vitro, we then prepared laminated sheets of myoblasts (C2C12) and fibroblasts (NIH3T3) (a pseudo MTJ model). Myo did not affect the expression of Pax7 and desmin (markers of muscle development), scleraxis and temonodulin (markers of tendon development), or Sox9 (a common marker of muscle and tendon development) in the cell sheets. However, Myo changed the nuclear morphology of scleraxis-positive cells arrayed at the boundary between the myoblast sheet and the fibroblast sheet (aspect ratio of the cell nuclei, myostatin(+) vs. myostatin(-): p = 0.000134). Myo may strengthen the connection at the MTJ in the initial stages of growth and wound healing.
PMCID:10094852
PMID: 37047606
ISSN: 1422-0067
CID: 5464182

Lineage-specific mutation of Lmx1b provides new insights into distinct regulation of suture development in different areas of the calvaria

Cabrera Pereira, Angel; Dasgupta, Krishnakali; Ho, Thach-Vu; Pacheco-Vergara, Maria; Kim, Julie; Kataria, Niam; Liang, Yaowei; Mei, Jeslyn; Yu, Jinyeong; Witek, Lukasz; Chai, Yang; Jeong, Juhee
The calvaria (top part of the skull) is made of pieces of bone as well as multiple soft tissue joints called sutures. The latter is crucial to the growth and morphogenesis of the skull, and thus a loss of calvarial sutures can lead to severe congenital defects in humans. During embryogenesis, the calvaria develops from the cranial mesenchyme covering the brain, which contains cells originating from the neural crest and the mesoderm. While the mechanism that patterns the cranial mesenchyme into bone and sutures is not well understood, function of Lmx1b, a gene encoding a LIM-domain homeodomain transcription factor, plays a key role in this process. In the current study, we investigated a difference in the function of Lmx1b in different parts of the calvaria using neural crest-specific and mesoderm-specific Lmx1b mutants. We found that Lmx1b was obligatory for development of the interfrontal suture and the anterior fontanel along the dorsal midline of the skull, but not for the posterior fontanel over the midbrain. Also, Lmx1b mutation in the neural crest-derived mesenchyme, but not the mesoderm-derived mesenchyme, had a non-cell autonomous effect on coronal suture development. Furthermore, overexpression of Lmx1b in the neural crest lineage had different effects on the position of the coronal suture on the apical part and the basal part. Other unexpected phenotypes of Lmx1b mutants led to an additional finding that the coronal suture and the sagittal suture are of dual embryonic origin. Together, our data reveal a remarkable level of regional specificity in regulation of calvarial development.
PMCID:10427921
PMID: 37593235
ISSN: 1664-042x
CID: 5618602

Candidate positive targets of LHX6 and LHX8 transcription factors in the developing upper jaw

Cesario, Jeffry; Ha, Sara; Kim, Julie; Kataria, Niam; Jeong, Juhee
Craniofacial development is controlled by a large number of genes, which interact with one another to form a complex gene regulatory network (GRN). Key components of GRN are signaling molecules and transcription factors. Therefore, identifying targets of core transcription factors is an important part of the overall efforts toward building a comprehensive and accurate model of GRN. LHX6 and LHX8 are transcription factors expressed in the oral mesenchyme of the first pharyngeal arch (PA1), and they are crucial regulators of palate and tooth development. Previously, we performed genome-wide transcriptional profiling and chromatin immunoprecipitation to identify target genes of LHX6 and LHX8 in PA1, and described a set of genes repressed by LHX. However, there has not been any discussion of the genes positively regulated by LHX6 and LHX8. In this paper, we revisited the above datasets to identify candidate positive targets of LHX in PA1. Focusing on those with known connections to craniofacial development, we performed RNA in situ hybridization to confirm the changes in expression in Lhx6;Lhx8 mutant. We also confirmed the binding of LHX6 to several putative enhancers near the candidate target genes. Together, we have uncovered novel connections between Lhx and other important regulators of craniofacial development, including Eya1, Barx1, Rspo2, Rspo3, and Wnt11.
PMID: 34861428
ISSN: 1872-7298
CID: 5066072

R-Spondin 3 Regulates Mammalian Dental and Craniofacial Development

Dasgupta, Krishnakali; Cesario, Jeffry M; Ha, Sara; Asam, Kesava; Deacon, Lindsay J; Song, Ana H; Kim, Julie; Cobb, John; Yoon, Jeong Kyo; Jeong, Juhee
Development of the teeth requires complex signaling interactions between the mesenchyme and the epithelium mediated by multiple pathways. For example, canonical WNT signaling is essential to many aspects of odontogenesis, and inhibiting this pathway blocks tooth development at an early stage. R-spondins (RSPOs) are secreted proteins, and they mostly augment WNT signaling. Although RSPOs have been shown to play important roles in the development of many organs, their role in tooth development is unclear. A previous study reported that mutating Rspo2 in mice led to supernumerary lower molars, while teeth forming at the normal positions showed no significant anomalies. Because multiple Rspo genes are expressed in the orofacial region, it is possible that the relatively mild phenotype of Rspo2 mutants is due to functional compensation by other RSPO proteins. We found that inactivating Rspo3 in the craniofacial mesenchyme caused the loss of lower incisors, which did not progress beyond the bud stage. A simultaneous deletion of Rspo2 and Rspo3 caused severe disruption of craniofacial development from early stages, which was accompanied with impaired development of all teeth. Together, these results indicate that Rspo3 is an important regulator of mammalian dental and craniofacial development.
PMCID:8395884
PMID: 34449628
ISSN: 2221-3759
CID: 5018142

Mice with deletion of PKA regulatory subunit1A in osteoblasts show severe bone pathology [Meeting Abstract]

Le, Henaff C; Finnie, B; Johnson, J; Nahaei, Y; He, Z; Dasgupta, K; Jeong, J; Warshaw, J; Kronenberg, H M; Kirschner, L S; Partridge, N C
Parathyroid hormone (PTH) was the first osteoanabolic hormone for treating osteoporosis. We have previously shown that PTH acts through PTHR1 and protein kinase A (PKA) activation to regulate osteoblastic gene expression. Our study aimed to elucidate the effects of increased PKA activity and better understand the actions of PTH (1-34) in bone. Tamoxifen (1mg/10g) was injected weekly to 1 or 5 month-old C57Bl/6J male col1CREERT/Prkar1afl/fl mice or Prkar1afl/fl mice as controls for 3-4 weeks to delete the PKA regulatory subunit 1A in osteoblasts and increase PKA activity. At both ages, col1CREERT/Prkar1afl/fl mice demonstrated bone pathologies in their skulls, femurs and vertebrae and tumors in their tails (Figure 1). MicroCT showed cortical bone breakdown with apparent trabecular bone in the cortical area in femurs and vertebrae and expansion of bone in skulls. Deletion of Prkar1a increased bone turnover with a huge increase in osteoblast activity shown by serum-P1NP levels (6.5-13 fold), only single fluorescent labeling and a substantial increase in osteoclast activity shown by CTX levels (4.4-12 fold) and TRAP staining. Surprisingly, the col1CREERT/Prkar1afl/fl skulls showed thicker calvariae, shown by alizarin red staining and muCT but no changes in mandibles or teeth. Col1CREERT/Prkar1afl/fl mice had tumors in their tails evident by an invasion of stromal and osteoclastic cells but with intact growth plate, cartilage and intervertebral discs. In conclusion, high PKA activity in osteoblasts appears to be involved with high bone turnover and pathological events mimicking hyperparathyroidism, Jansen's metaphyseal chondrodysplasia or McCune-Albright syndrome. [Formula presented]
Copyright
EMBASE:2008367208
ISSN: 2352-1872
CID: 4701782

Switching of Sox9 expression during musculoskeletal system development

Nagakura, Ryotaro; Yamamoto, Masahito; Jeong, Juhee; Hinata, Nobuyuki; Katori, Yukio; Chang, Wei-Jen; Abe, Shinichi
The musculoskeletal system, which comprises muscles, tendons, and bones, is an efficient tissue complex that coordinates body movement and maintains structural stability. The process of its construction into a single functional and complex organization is unclear. SRY-box containing gene 9 (Sox9) is expressed initially in pluripotent cells and subsequently in ectodermal, endodermal, and mesodermal derivatives. This study investigated how Sox9 controls the development of each component of the musculoskeletal system. Sox9 was expressed in MTJ, tendon, and bone progenitor cells at E13 and in bone at E16. We detected Sox9 expression in muscle progenitor cells using double-transgenic mice and myoblastic cell lines. However, we found no Sox9 expression in developed muscle. A decrease in Sox9 expression in muscle-associated connective tissues, tendons, and bones led to hypoplasia of the cartilage and its attachment to tendons and muscle. These results showed that switching on Sox9 expression in each component (muscle, tendon, and bone) is essential for the development of the musculoskeletal system. Sox9 is expressed in not only tendon and bone progenitor cells but also muscle progenitor cells, and it controls musculoskeletal system development.
PMID: 32439983
ISSN: 2045-2322
CID: 4447252

Morphological association between the muscles and bones in the craniofacial region

Yamamoto, Masahito; Takada, Hiromasa; Ishizuka, Satoshi; Kitamura, Kei; Jeong, Juhee; Sato, Masaki; Hinata, Nobuyuki; Abe, Shinichi
The strains of inbred laboratory mice are isogenic and homogeneous for over 98.6% of their genomes. However, geometric morphometric studies have demonstrated clear differences among the skull shapes of various mice strains. The question now arises: why are skull shapes different among the mice strains? Epigenetic processes, such as morphological interaction between the muscles and bones, may cause differences in the skull shapes among various mice strains. To test these predictions, the objective of this study is to examine the morphological association between a specific part of the skull and its adjacent muscle. We examined C57BL6J, BALB/cA, and ICR mice on embryonic days (E) 12.5 and 16.5 as well as on postnatal days (P) 0, 10, and 90. As a result, we found morphological differences between C57BL6J and BALB/cA mice with respect to the inferior spine of the hypophyseal cartilage or basisphenoid (SP) and the tensor veli palatini muscle (TVP) during the prenatal and postnatal periods. There was a morphological correlation between the SP and the TVP in the C57BL6J, BALB/cA, and ICR mice during E15 and P0. However, there were not correlation between the TVP and the SP during P10. After discectomy, bone deformation was associated with a change in the shape of the adjacent muscle. Therefore, epigenetic modifications linked to the interaction between the muscles and bones might occur easily during the prenatal period, and inflammation seems to allow epigenetic modifications between the two to occur.
PMID: 31923241
ISSN: 1932-6203
CID: 4257022

Osteoblastic Deletion of PKA Regulatory Subunit1A Causes Severe Bone Pathology in Mice [Meeting Abstract]

Le Henaff, Carole; Finnie, Brandon; Johnson, Joshua; Nahaei, Yasaman; He, Zhiming; Dasgupta, Krishnakali; Jeong, Juhee; Warshaw, Johanna; Kronenberg, Henry M.; Kirschner, Lawrence S.; Partridge, Nicola C.
ISI:000593119300093
ISSN: 0884-0431
CID: 4736562

Molecular patterning of the embryonic cranial mesenchyme revealed by genome-wide transcriptional profiling

Dasgupta, Krishnakali; Chung, Jong Uk; Asam, Kesava; Jeong, Juhee
In the head of an embryo, a layer of mesenchyme surrounds the brain underneath the surface ectoderm. This cranial mesenchyme gives rise to the meninges, the calvaria (top part of the skull), and the dermis of the scalp. Abnormal development of these structures, especially the meninges and the calvaria, is linked to significant congenital defects in humans. It has been known that different areas of the cranial mesenchyme have different fates. For example, the calvarial bone develops from the cranial mesenchyme on the baso-lateral side of the head just above the eye (supraorbital mesenchyme, SOM), but not from the mesenchyme apical to SOM (early migrating mesenchyme, EMM). However, the molecular basis of this difference is not fully understood. To answer this question, we compared the transcriptomes of EMM and SOM using high-throughput sequencing (RNA-seq). This experiment identified a large number of genes that were differentially expressed in EMM and SOM, and gene ontology analyses found very different terms enriched in each region. We verified the expression of about 40 genes in the head by RNA in situ hybridization, and the expression patterns were annotated to make a map of molecular markers for 6 subdivisions of the cranial mesenchyme. Our data also provided insights into potential novel regulators of cranial mesenchyme development, including several axon guidance pathways, lectin complement pathway, cyclic-adenosine monophosphate (cAMP) signaling pathway, and ZIC family transcription factors. Together, information in this paper will serve as a unique resource to guide future research on cranial mesenchyme development.
PMID: 31351040
ISSN: 1095-564x
CID: 3988522

Developmental Biology of the Meninges

Dasgupta, Krishnakali; Jeong, Juhee
The meninges are membranous layers surrounding the central nervous system. In the head, the meninges lie between the brain and the skull, and interact closely with both during development. The cranial meninges originate from a mesenchymal sheath on the surface of the developing brain, called primary meninx, and undergo differentiation into three layers with distinct histological characteristics: the dura mater, the arachnoid mater, and the pia mater. While genetic regulation of meningeal development is still poorly understood, mouse mutants and other models with meningeal defects have demonstrated the importance of the meninges to normal development of the calvaria and the brain. For the calvaria, the interactions with the meninges are necessary for the progression of calvarial osteogenesis during early development. In later stages, the meninges control the patterning of the skull and the fate of the sutures. For the brain, the meninges regulate diverse processes including cell survival, cell migration, generation of neurons from progenitors, and vascularization. Also, the meninges serve as a stem cell niche for the brain in the postnatal life. Given these important roles of the meninges, further investigation into the molecular mechanisms underlying meningeal development can provide novel insights into the coordinated development of the head.
PMID: 30801905
ISSN: 1526-968x
CID: 3698952