Abstract
Protein translation regulation has essential roles in inflammatory responses, cancer initiation and the pathogenesis of several neurodegenerative disorders. However, the role of the regulation of protein translation in mammalian skeleton development has been rarely elaborated. Here we report that the lack of the RNA-binding protein sterile alpha motif domain containing protein 4 (SAMD4) resulted in multiple developmental defects in mice, including delayed bone development and decreased osteogenesis. Samd4-deficient mesenchymal progenitors exhibit impaired osteoblast differentiation and function. Mechanism study demonstrates that SAMD4 binds the Mig6 mRNA and inhibits MIG6 protein synthesis. Consistent with this, Samd4-deficient cells have increased MIG6 protein level and knockdown of Mig6 rescues the impaired osteogenesis in Samd4-deficient cells. Furthermore, Samd4-deficient mice also display chondrocyte defects, which is consistent with the regulation of MIG6 protein level by SAMD4. These findings define SAMD4 as a previously unreported key regulator of osteoblastogenesis and bone development, implying that regulation of protein translation is an important mechanism governing skeletogenesis and that control of protein translation could have therapeutic potential in metabolic bone diseases, such as osteoporosis.
Highlights
Protein translational regulation of gene expression is necessary for the ability of cells to rapidly respond to the changes in the environment [1], especially in response to stress-causing stimuli, such as ultraviolet irradiation, temperature changes, nutrient limitation, oxidative stress and various drugs or toxins [2, 3]
sterile alpha motif domain containing 4 (Samd4) is widely expressed in different tissues (Figure 1c), and the insertion of PB transposon at Samd4 locus resulted in a dramatic reduction of Samd4 transcript and protein level in mice homozygous for the PB transposon allele (Samd4PB/PB; Figure 1d and e)
Analysis of littermates born to male and female mice heterozygous for the Samd4 PB allele (Samd4PB/+) revealed that Samd4PB/PB mice exhibited a large reduction in body size and weight (Figure 1f and g) and had a shortened lifespan when compared with age- and sex-matched wild-type (WT) littermates (Figure 1h)
Summary
Protein translational regulation of gene expression is necessary for the ability of cells to rapidly respond to the changes in the environment [1], especially in response to stress-causing stimuli, such as ultraviolet irradiation, temperature changes, nutrient limitation, oxidative stress and various drugs or toxins [2, 3]. Skeleton development and remodeling are critical for maintenance of the biomechanical properties of bone [9]. The long bones are mainly formed through endochondral bone formation and are maintained by bone remodeling [9]. Osteoblasts, a group of specialized mesenchymal cells, are crucial for the mineralization of the embryonic skeleton and bone mass maintenance during postnatal bone remodeling [11, 12]. Little is known about whether protein translational regulation acts on this process
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