Recombinant Human DNER Fc Chimera Protein, CF

DNER (Delta/Notch-like EGF-related receptor), also known as BET (brain-specific EGF-like transmembrane protein), is a type I transmembrane glycoprotein of the Notch/Delta family (1, 2). In the mouse, DNER has been detected as 90, 120 and 150 kDa forms which are probably variably glycosylated (1, 2). DNER is specifically expressed on nonaxonal areas of post-mitotic neurons, especially Purkinje cells, but also cortical and hippocampal pyramidal neurons and immature cerebellar granule cells (1 ‑ 5). After expression on the cell surface, DNER is removed from axonal membranes, but remains on somatodendritic membranes (1, 3, 6). A portion of DNER is found within endosomes (1, 3, 6). Human DNER cDNA encodes 737 amino acids (aa) that include a 25 aa signal sequence, a 615 aa extracellular domain (ECD) containing ten distinct Delta/Notch-like EGF‑like repeats, a 21 aa transmembrane sequence, and a 76 aa cytoplasmic domain. The human DNER ECD shares 89%, 89% and 88% aa sequence identity with mouse, rat and bovine DNER, respectively. DNER is a Notch ligand, but is considered a non-classical ligand because it lacks the usual DSL Notch binding motif (5, 7). Instead, Notch interacts with the two EGF‑like repeats closest to the N-terminus of DNER (5). Mice lacking DNER show impaired cerebellar functions and delayed Purkinje cell-mediated maturation of Notch-expressing Bergmann glia during cerebellar development (4, 5). DNER associates with protein tyrosine phosphatase zeta (PTP zeta), which is the receptor of pleiotrophin (PTN). PTP zeta-PTN-DNER signaling has been implicated in the regulation of neuritogenesis (3). Expression of DNER in glioblastoma stem-like cells inhibits formation of neurospheres in vitro,  while in vivo it induces differentiation and inhibits growth of xenografts, thus acting as a tumor suppressor (7). Expression of DNER in adipose‑derived human mesenchymal stem cells and mouse auditory hair cells have also been shown (8, 9).