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Tafa is a family of small secreted proteins with conserved cysteine residues and restricted expression in the brain.It is composed of five highly homologous genes referred to as Tafa-1 to-5.Among them,Tafa-2 is identified as one of the potential genes responsible for intellectual deficiency in a patient with mild mental retardation.To investigate the biological function of Tafa-2 in vivo,Tafa-2 knockout mice were generated.The mutant mice grew and developed normally but exhibited impairments in spatial leaing and memory in Morris water maze test and impairments in short-and long-term memory in novel object recognition test,accompanied with increased level of anxiety-like behaviors in open-field test and elevated plus maze test,and decreased level of depression-like behaviors in forced-swim test and tail-suspension test.Further examinations revealed that Tafa-2 deficiency causes severe neuronal reduction and increased apoptosis in the brain of Tafa-2-/-mice via downregulation of PI3K/Akt and MAPK/Erk pathways.Conformably,the expression levels of CREB target genes including BDNF,c-fos and NF1,and CBPwere found to be reduced in the brain of Tafa-2-/-mice.Taken together,our data indicate that Tafa-2 may function as a neurotrophic factor essential for neuronal survival and neurobiological functions.