Abstract
Bone morphogenetic protein 7 (BMP7) belongs to the transforming growth factor β (TGF-β) family, which not only induces cartilage and bone formation, but also regulates eye development and melanoma tumorigenesis in mammals. In teleosts, BMP7 differentiates into two subtypes, bmp7a and bmp7b, which have clearly differentiated structures. To fully understand the functional differentiation of bmp7a and bmp7b in fish species, we successfully constructed bmp7a and bmp7b gene deletion mutants in zebrafish using CRISPR/Cas9-mediated gene editing technology. Our results showed that bmp7a mutation caused abnormal development of the embryo’s dorsal-ventral pattern that led to death; bmp7b mutation induced growth inhibition and increased melanin production in the skin and eye of mutants. Histological analysis revealed that melanin in the retina of the eyes in bmp7b mutants increased, and behavioral observation showed that the vision and sensitivity to food of the mutants were reduced. Transcriptome analysis of the skin and eye tissues showed that the expression changes of wnt7ba and gna14 in bmp7b mutants might promote the increase of melanin. Additionally, the eye transcriptome analysis indicated that changes in the structure of the eyes in bmp7b mutants led to defects in phototransduction, and seven DEGs (rgs9a, rgs9b, rcvrn2, guca1d, grk1b, opn1mw4, and gc2) were identified as key candidate genes that affected the photonic response of the eyes. The study revealed the functional differentiation of bmp7a and bmp7b in teleosts and the first report about the inhibitory effect of bmp7b on melanogenesis may provide useful information for the future research on human melanoma-related diseases.
Highlights
Bone morphogenetic protein 7 [BMP7 (OP-1)], a member of the transforming growth factor-β (TGF-β) superfamily, is a 35 kDa homodimeric protein that is involved in the differentiation of mesenchymal cells into osteoblasts and promotes ectopic bone formation (Celeste et al, 1990; Ozkaynak et al, 1990; Ducy and Karsenty, 2000)
The evolutionary origin and phylogenetic distribution of BMP7 showed that BMP7 orthologs, which evolved from the same ancestral gene family of vertebrates, had duplications in teleosts after the evolution of L. chalumnae, named bmp7a and bmp7b
The gene sequence and structure analysis of BMP7 genes showed that the zebrafish bmp7b gene is highly homologous to the BMP7 gene in humans and mammals
Summary
Bone morphogenetic protein 7 [BMP7 (OP-1)], a member of the transforming growth factor-β (TGF-β) superfamily, is a 35 kDa homodimeric protein that is involved in the differentiation of mesenchymal cells into osteoblasts and promotes ectopic bone formation (Celeste et al, 1990; Ozkaynak et al, 1990; Ducy and Karsenty, 2000). BMP7 mainly binds to type I and type II BMP receptors expressed on the cell surface to activate receptorregulated SMADs (R-SMADs, including SMAD1, 2, 3, 5, and 8). In addition to bone formation, previous studies have proved that BMP7 has an indispensable role in the growth, differentiation, and apoptosis of various tissues (Ducy and Karsenty, 2000). BMP7 is involved in the regulation of hair follicle development and hair growth (Lv et al, 2016), and the size and spatial distribution of hair (Michon et al, 2008). BMP7 was shown to be involved in regulating the production of melanin and was strongly expressed in metastatic and primary melanoma (Rothhammer et al, 2005; Vitic et al, 2021)
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