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 producing OPN + milk and OPN knockout (KO) dams producing OPN − milk nursed WT pups (OPN +/+ ), yielding 2 pup treatment groups, OPN + OPN +/+ and OPN − 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 of milk by WT and KO dams. The ability of ingested milk OPN to enter the brain was revealed by appearance of orally gavaged [ 125 I]‐labeled and antibody‐probed milk OPN in brains of pups. Brain OPN mRNA levels were similar in both nursed groups, but the brain OPN protein level was significantly lower in the OPN − OPN +/+ group at postnatal days 6 and 8. Behavior tests showed impaired memory and learning ability in OPN − 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 PI3K7Akt signaling. We concluded that milk OPN can play an important role in brain development and behavior in infancy by promoting myelination.—Jiang, R., Prell, C., Lönnerdal, B. Milk osteopontin promotes brain development by up‐regulating osteopontin in the brain in early life. FASEB J. 33, 1681–1694 (2019). www.fasebj.org