Knockout of the prion protein (PrP)-like Sprn gene does not produce embryonic lethality in combination with PrPC-deficiency

The Sprn gene encodes Shadoo (Sho), a glycoprotein with biochemical properties similar to the unstructured region of cellular prion protein (PrPC). Sho has been considered a candidate for the hypothetical pi protein that supplies a PrPC-like function to maintain the viability of Prnp(0/0) mice lacking the PrPC protein. To understand these relationships more clearly we probed the cell biology of Sho and created knockout mice. Besides full-length and a C1 C-terminal fragment, we describe a 6-kDa N-terminal Sho neuropeptide, N1, which is present in membrane-enriched subcellular fractions of wild-type mice. Sprn null alleles were produced that delete all protein coding sequences yet spare the Mtg1 gene transcription unit that overlaps the Sprn 3' UTR; the resulting mice bred to homozygosity were viable and fertile, although Sprn(0/0) mice maintained in two genetic backgrounds weighed less than wildtype mice. Lack of Sho protein did not affect prion incubation time. Contrasting with lethality reported for knockdown of expression in Prnp(0/0) embryos using lentiviruses targeted against the Sprn 3' UTR, we established that double-knockout mice deficient in both Sho and PrPC are fertile and viable up to 690 d of age. Our data reduce the impetus for equating Sho with the notional pi protein and are not readily reconciled with hypotheses wherein expression of PrPC and Sho are both required for completion of embryogenesis. Alternatively, and in accord with some reports for PrPC, we infer that Sho's activity will prove germane to the maintenance of neuronal viability in postnatal life.