Unraveling the Connection between Fibroblast Growth Factor and Bone Morphogenetic Protein Signaling

Schliermann, Anna; Nickel, J. Curtis

doi:10.3390/ijms19103220

Cited by 23 publications

(22 citation statements)

References 109 publications

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“…FGF10 derived from the developing cristae affects vestibular morphogenesis (Pauley et al, 2003). Conceivably, ectopic expression of Fgf8 in the ventral and of Fgf3 in the posteriordorso-medial region of Tbx2/3cDKO otocysts may constitute novel signalling centres that directly interfere with regionalisation along the otocyst axes, and/or affect the activity of other signalling pathways, particularly BMP signalling, required for otocyst patterning as shown in many other developmental contexts (reviewed by Schliermann and Nickel, 2018;Teven et al, 2014). We conclude that TBX2 and TBX3 are essential regulators of signalling activities that confer regional identities important for localised outgrowth in the otocyst.…”

Section: Discussionmentioning

confidence: 99%

Regulation of otocyst patterning by Tbx2 and Tbx3 is required for inner ear morphogenesis in the mouse

et al. 2021

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All epithelial components of the inner ear, including sensory hair cells and innervating afferent neurons, arise by patterning and differentiation of epithelial progenitors residing in a simple sphere, the otocyst. Here, we identify the transcriptional repressors TBX2 and TBX3 as novel regulators of these processes in the mouse. Ablation of Tbx2 from the otocyst led to cochlear hypoplasia whereas loss of Tbx3 was associated with vestibular malformations. The loss of function of both genes (Tbx2/3cDKO) prevented inner ear morphogenesis at midgestation, resulting in indiscernible cochlear and vestibular structures at birth. Morphogenetic impairment occurred concommitantly with increased apoptosis in ventral and lateral regions of Tbx2/3cDKO otocysts around E10.5. Expression analyses revealed partly disturbed regionalisation, and a posterior-ventral expansion of the neurogenic domain in Tbx2/3cDKO otocysts at this stage. We provide evidence that repression of FGF signalling by TBX2 is important to restrict neurogenesis to the anterior-ventral otocyst and implicate another T-box factor, TBX1, as a critical mediator in this regulatory network.

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Section: Discussionmentioning

confidence: 99%

Regulation of otocyst patterning by Tbx2 and Tbx3 is required for inner ear morphogenesis in the mouse

et al. 2021

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“…Crosstalk between TGFβ/BMP signaling and Ras/MAPK system has been noted in other systems as well, for example, in malignancies where BMP signaling has inhibitory effects and is counteracted by Ras and MAPK signaling (25,26). It is conceivable that such crosstalk takes place in other pathological processes, such as DSLD, and likely in normal physiological events as well (27).…”

Section: Discussionmentioning

confidence: 98%

Differential gene expression in skin RNA of horses affected with degenerative suspensory ligament desmitis

Haythorn¹,

Young²,

Stanton³

et al. 2020

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Background Equine Degenerative Suspensory Desmitis (DSLD) is a systemic connective tissue disorder first identified in Peruvian Paso horses, but afflicting other horse breeds as well. Inappropriate accumulation of proteoglycans in connective tissues, most prominently in tendons and ligaments leads to lameness and pain. It is largely unknown what drives the overproduction of proteoglycans, but our previous data suggest involvement of bone morphogenetic protein 2 (BMP2), a member of the transforming growth factor β (TGFβ) family, impacting synthesis of proteoglycans. To identify potential players in pathogenesis of DSLD a new approach utilizing next generation sequencing was undertaken. Methods Next generation sequencing was performed using RNA extracted from skin biopsies of six control Peruvian Pasos and six horses with DSLD (4 Peruvian Pasos and 2 Warmbloods). The CuffDiff result sets were validated with algorithms used to run them. This was based on the determined False Discovery Rates derived from the P-values adjusted for multiple testing for any given result. Results Bioinformatics analysis of transcriptomes revealed differential expression of over 1500 genes, including increased expression of genes for several growth factors (BMP2, FGF5, CTGF, members of the EGF family), of mediators of signaling (Fos, Myc, MAPK system), and keratins. Two genes encoding for enzymes involved in synthesis of hyaluronan were overexpressed. Gene expression was decreased for protein cores of many proteoglycans, several growth factors, most collagens and many peptides with immune function. Conclusions The overexpression of BMP2 correlates well with our previous data. However, the decrease in expression of numerous proteoglycans was unexpected. A mutation in a gene of a less characterized proteoglycan and/or glycosyltransferase with subsequent increased production of hyaluronan and/or a proteoglycan(s) undetected in our study could account for the systemic proteoglycan deposition. Decreased collagen gene expression indicates abnormal connective tissue metabolism. The increased expression of keratin genes and FGF5 supports reports of skin abnormalities in DSLD. Underexpression of immune function genes corresponds with lack of inflammation in DSLD tissues. Finally, though the proteoglycan and/or glycosaminoglycan abundant in DSLD has not been identified, we validated our previous data, including overexpression of BMP2, and systemic nature of DSLD due to disturbed metabolism of the extracellular matrix.

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“…Instead, the observed overexpression of genes encoding for Fos and many mediators in the MAPK pathways indicates that MAPK pathway plays an important role in inappropriate expression and activity of BMP2 in DSLD. Crosstalk between TGFβ/BMP signaling and Ras/MAPK system has been noted in other systems as well [ 31 – 33 ].…”

Section: Discussionmentioning

confidence: 99%

Differential gene expression in skin RNA of horses affected with degenerative suspensory ligament desmitis

et al. 2020

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Background Equine degenerative suspensory ligament desmitis (DSLD) is a systemic connective tissue disorder first identified in Peruvian Paso horses but afflicting other horse breeds as well. Inappropriate accumulation of proteoglycans in connective tissues, most prominently in tendons and ligaments, leads to progressive and debilitating lameness and pain. It is largely unknown what drives the overproduction of proteoglycans, but our previous studies suggest involvement of bone morphogenetic protein 2 (BMP2), a member of the transforming growth factor-β (TGFβ) family, impacting synthesis of proteoglycans. To identify potential players in pathogenesis of DSLD a new approach utilizing next generation sequencing was undertaken. Methods Next generation sequencing was performed using RNA extracted from skin biopsies of six control Peruvian Pasos and six horses with DSLD (4 Peruvian Pasos and 2 warmbloods). The CuffDiff result sets were validated with algorithms used to run them. This was based on the determined false discovery rates derived from the P values adjusted for multiple testing for any given result. Results Bioinformatics analysis of transcriptomes revealed differential expression of over 1500 genes, including increased expression of genes for several growth factors (most prominently BMP2, FGF5, CTGF, many members of the EGF family), and mediators of signaling (Fos, Myc, MAPK system), and keratins. Two genes encoding for enzymes involved in synthesis of hyaluronan were also overexpressed. Gene expression was decreased for protein cores of many proteoglycans, several growth factors, most collagens, and many peptides with immune function. Conclusions The overexpression of BMP2 correlates well with our previous data. However, the decrease in expression of numerous proteoglycans was unexpected. A mutation in a gene of a less characterized proteoglycan and/or glycosyltransferase with subsequent increased production of hyaluronan and/or a proteoglycan(s) undetected in our study could account for the systemic proteoglycan deposition. Decreased collagen gene expression indicates abnormal connective tissue metabolism. The increased expression of keratin genes and FGF5 supports reports of skin abnormalities in DSLD. Underexpression of immune function genes corresponds with lack of inflammation in DSLD tissues. Finally, though the proteoglycan and/or glycosaminoglycan abundant in DSLD has not been identified, we validated our previous data, including overexpression of BMP2, and systemic nature of DSLD due to disturbed metabolism of the extracellular matrix.

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Unraveling the Connection between Fibroblast Growth Factor and Bone Morphogenetic Protein Signaling

Cited by 23 publications

References 109 publications

Regulation of otocyst patterning by Tbx2 and Tbx3 is required for inner ear morphogenesis in the mouse

Regulation of otocyst patterning by Tbx2 and Tbx3 is required for inner ear morphogenesis in the mouse

Differential gene expression in skin RNA of horses affected with degenerative suspensory ligament desmitis

Differential gene expression in skin RNA of horses affected with degenerative suspensory ligament desmitis

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