Abstract
Skeletal development throughout the embryonic and postnatal phases is a dynamic process, based on bone remodeling and the balance between the activities of osteoclasts and osteoblasts modulating skeletal homeostasis. The Notch signaling pathway is a regulator of several developmental processes, and plays a crucial role in the development of the human skeleton by regulating the proliferation and differentiation of skeletal cells. The Delta Like-1 (DLL1) gene plays an important role in Notch signaling. We propose that an identified alteration in DLL1 protein may affect the downstream signaling. In this article, we present for the first time two siblings with a mutation in the DLL1 gene, presenting with congenital vertebral malformation. Using variable in silico prediction tools, it was predicted that the variant was responsible for the development of disease. Quantitative reverse-transcription polymerase chain reaction (PCR) for the Notch signaling pathway, using samples obtained from patients, showed a significant alteration in the expression of various related genes. Specifically, the expression of neurogenic locus notch homolog protein 1, SNW domain-containing protein 1, disintegrin, and metalloproteinase domain-containing proteins 10 and 17, was upregulated. In contrast, the expression of HEY1, HEY2, adenosine deaminase (ADA), and mastermind-like-1 (MAML-1) was downregulated. Furthermore, in a phosphokinase array, four kinases were significantly changed in patients, namely, p27, JANK1/2/3, mitogen- and stress-activated protein kinases 1 and 2, and focal adhesion kinase. Our results suggest an implication of a DLL1 defect related to the Notch signaling pathway, at least in part, in the morphologic abnormality observed in these patients. A limitation of our study was the low number of patients and samples. Further studies in this area are warranted to decipher the link between a DLL1 defect and skeletal abnormality.
Highlights
IntroductionMesenchymal precursor bone cells determine the skeletal structure and characteristics in terms of shape, size, orientation, and integration
During embryonic development, mesenchymal precursor bone cells determine the skeletal structure and characteristics in terms of shape, size, orientation, and integration
Human bone homeostasis is modulated by the Notch signaling pathway through a regulatory effect on the function and differentiation of the osteoblast and osteoclast lineages
Summary
Mesenchymal precursor bone cells determine the skeletal structure and characteristics in terms of shape, size, orientation, and integration. Human bone tissue is a dynamic structure that is continuously remodeled and balanced between degradation and renewal. This process is modulated by two major types of bone cells, namely, osteoblasts and osteoclasts of mesenchymal and hematopoietic origin, respectively (Panaroni et al, 2014). Extracellular and intracellular signals are required for the differentiation of mesenchymal cells to contribute to the osteoblastic lineage (Canalis et al, 2003). The osteoblast differentiation and bone modeling pathway are complex. One of the critical regulators of tissue renewal and embryonic development is the Notch signaling pathway, which mediates cell-tocell interactions in this process (Zanotti and Canalis, 2012). The definite mechanisms involved in this diverse and complex role of Notch remain to be clarified (Muguruma et al, 2017)
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