Milk osteopontin promotes brain development by up-regulating osteopontin in the brain in early life

Abstract

Osteopontin (OPN) is a pleiotropic protein and is abundantly present in milk. Its functions include immune modulation and cellular proliferation and differentiation. OPN is highly expressed in the brain. We investigated the effects of milk-derived OPN on brain development of mouse pups. Wild-type (WT) dams producingOPN+ milk andOPNknockout (KO) dams producingOPN2 milk nursedWT pups (OPN+/+), yielding 2 pup treatment groups, OPN+ OPN+/+ and OPN2 OPN+ /+, for comparison. Preliminary studies supported use of this model by showing high concentrations of OPN in milk of WT dams and no OPN in milk of OPN KO dams, and production of similar amounts ofmilk byWTandKOdams.The ability of ingestedmilkOPNto enter the brainwas revealed by appearance of orally gavaged [125I]-labeled and antibody-probed milk OPN in brains of pups. Brain OPNmRNA levels were similar in both nursed groups, but the brain OPN protein levelwas significantly lower in theOPN2 OPN+/+ group at postnatal days 6 and 8. Behavior tests showed impairedmemory and learning ability in OPN2 OPN+/+ pups. In addition, our study revealed increased expression of myelination-related proteins and elevated proliferation and differentiation of NG-2 glia into oligodendrocytes in the brain of OPN+ OPN+/+ pups, accompanied by increased activation of ERK-1/2 and PI3K/Akt signaling.We concluded thatmilkOPN can play an important role in brain development and behavior in infancy by promoting myelination.