title: Knockout of the prion protein (PrP)-like Sprn gene does not produce embryonic lethality in combination with PrP(C)-deficiency.
abstract: The Sprn gene encodes Shadoo (Sho), a glycoprotein with biochemical properties similar to the unstructured region of cellular prion protein (PrP(C)). Sho has been considered a candidate for the hypothetical π protein that supplies a PrP(C)-like function to maintain the viability of Prnp(0/0) mice lacking the PrP(C) 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 wild-type 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 PrP(C) are fertile and viable up to 690 d of age. Our data reduce the impetus for equating Sho with the notional π protein and are not readily reconciled with hypotheses wherein expression of PrP(C) and Sho are both required for completion of embryogenesis. Alternatively, and in accord with some reports for PrP(C), we infer that Sho's activity will prove germane to the maintenance of neuronal viability in postnatal life.
authors.affiliation: Centre for Prions and Protein Folding Diseases, University of Alberta, Edmonton, AB, Canada T6G 2M8.
authors.forename: Nathalie
authors.initials: N
authors.lastname: Daude
authors.forename: Serene
authors.initials: S
authors.lastname: Wohlgemuth
authors.forename: Rebecca
authors.initials: R
authors.lastname: Brown
authors.forename: Rose
authors.initials: R
authors.lastname: Pitstick
authors.forename: Hristina
authors.initials: H
authors.lastname: Gapeshina
authors.forename: Jing
authors.initials: J
authors.lastname: Yang
authors.forename: George A
authors.initials: GA
authors.lastname: Carlson
authors.forename: David
authors.initials: D
authors.lastname: Westaway
mesh_terms: D000704:Analysis of Variance; D000818:Animals; D015153:Blotting, Western; D001835:Body Weight / Q000235:genetics; D002458:Cell Fractionation; D002470:Cell Survival / Q000235:genetics; D003433:Crosses, Genetic; D047108:Embryonic Development / Q000235:genetics*; D005328:Fetal Viability / Q000235:genetics*; D058851:GPI-Linked Proteins; D005822:Genetic Vectors / Q000235:genetics; D051379:Mice; D018345:Mice, Knockout; D009419:Nerve Tissue Proteins / Q000172:deficiency / Q000235:genetics*; D009474:Neurons / Q000502:physiology; D009479:Neuropeptides / Q000235:genetics / Q000378:metabolism*; D018621:PrPC Proteins / Q000235:genetics*
chemical_list: D058851:GPI-Linked Proteins; D009419:Nerve Tissue Proteins; D009479:Neuropeptides; D018621:PrPC Proteins; C523856:Sprn protein, mouse