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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.
Highlights
Collins, Robin and Di George syndromes, are associated with defects in neural crest (NC) development.[1]
Apoptosis among non-NC cells (NCCs) along the entire body axis is the same between heterozygous and homozygous embryos (Figure 4y). These results reveal that the increase in apoptotic cells observed in the rostral cephalic region of the Prtg À / À embryos during E9–E10, as shown in Figure 3, are likely to involve R-cephalic NC cells (CNCCs)
No difference in migration ability is detected in Prtg-null trunk NC cells (TNCCs) and non-TNCCs. These results suggest that decreased expression of both high-affinity a5- and b1integrin subunits might exacerbate the deficiency of integrin activity in Prtg-null rostral CNCCs (R-CNCCs)
Summary
Robin and Di George syndromes, are associated with defects in neural crest (NC) development.[1] In rodents, jaws and the skull vault are derived from the cephalic NC cells (CNCCs) and the head paraxial mesoderm cells.[2] In the mouse embryo, the rostral CNCCs (R-CNCCs) originate from NC between diencephalon to rhombomere 2 (r2) and undergo an epithelial–mesenchymal transition at embryonic day 8.5. In addition to CNCCs, a part of posterior skull vault and the majority of skeletons in posterior upper jaw are contributed by derivatives of head paraxial mesoderm.[8]. Many immunoglobulin family members are expressed in the developing nervous system with undefined functions. We explore functions of one immunoglobulin family member, namely protogenin (Prtg) protein. The participating molecules involved in Prtg signaling include Radil and high-affinity conformational forms of the a5b1-integrin
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