Protogenin prevents premature apoptosis of rostral cephalic neural crest cells by activating the α5β1-integrin

Abstract

The bones and connective tissues of the murine jaws and skull are partly derived from cephalic neural crest cells (CNCCs). Here, we report that mice deficient of protogenin (Prtg) protein, an immunoglobulin domain-containing receptor expressed in the developing nervous system, have impairments of the palatine and skull. Data from lineage tracing experiments, expression patterns of neural crest cell (NCC) marker genes and detection of apoptotic cells indicate that the malformation of bones in Prtg-deficient mice is due to increased apoptosis of rostral CNCCs (R-CNCCs). Using a yeast two-hybrid screening, we found that Prtg interacts with Radil, a protein previously shown to affect the migration and survival of NCCs in zebrafish with unknown mechanism. Overexpression of Prtg induces translocation of Radil from cytoplasm to cell membrane in cultured AD293 cells. In addition, overexpression of Prtg and Radil activates α5β1-integrins to high-affinity conformational forms, which is further enhanced by the addition of Prtg ligand ERdj3 into cultured cells. Blockage of Radil by RNA interference abolishes the effect of ERdj3 and Prtg on the α5β1-integrin, suggesting that Radil acts downstream of Prtg. Prtg-deficient R-CNCCs display fewer activated α5β1-integrins in embryos, and these cells show reduced migratory ability in in vitro transwell assay. These results suggest that the inside-out activation of the α5β1-integrin mediated by ERdj3/Prtg/Radil signaling is crucial for proper functions of R-CNCCs, and the deficiency of this pathway causes premature apoptosis of a subset of R-CNCCs and malformation of craniofacial structures.

Maintenance of Stem Cell Niche Integrity by a Novel Activator of Integrin Signaling

“…It has been shown to act as a co-chaperone in assisting proper protein folding in the ER and in increasing the activity and affinity of Hsp70 BiP for substrates [ 47 , 49 , 50 ]. It also acts as a secreted protein that modulates integrin affinity [ 51 ] and in modulating unfolded protein response [ 52 ]. However, roles of DNAJB11 in stem cell maintenance and spermatogenesis have not been established.…”

“…Interestingly, the human homolog of Shv, DNAJB11, has recently been identified in secretome profiling as a protein upregulated in oral cavity squamous cell carcinoma [ 68 ], as well as secreted during unfold protein response activation [ 52 ]. In addition, DNAJB11 has been shown to be secreted in mice and influences integrin signaling [ 51 , 69 ], suggesting that the functions of Shv may be evolutionarily conserved. Strikingly, we found that upregulation of Shv was sufficient to preserve the number of hub cells and GSCs that normally decline during aging.…”

Periodic mechanical stress induces the extracellular matrix expression and migration of rat nucleus pulposus cells by upregulating the expression of intergrin α1 and phosphorylation of downstream phospholipase Cγ1

“…Integrins are a family of adhesion proteins on the cell surface, which are important for cell adhesion, proliferation, apoptosis and migration ( 9 , 10 ). Integrins transfer extracellular mechanical signals into intracellular chemical signals, regulating cellular metabolism via the downstream signaling pathways ( 11 ).…”

Combining feature selection and shape analysis uncovers precise rules for miRNA regulation in Huntington’s disease mice

“…Nonetheless, it is interesting to note that some of the miRNA retained in the cortex were associated with neuronal homeostasis. Mir10a (paired with the TNF receptor superfamily member Tnfrsf11a/RANK, involved in inflammatory response in the mouse [62], and with protogenin Prtg, involved in neurogenesis and apoptosis [63,64]) and Mir10b (paired with protogenin Prtg) are associated with the modulation of brain cell migration and aging [65,66]. MiRNA322 (paired with protogenin Prtg) is associated with apoptosis and Alzheimer's disease (AD) [67].…”