The BMP2 nuclear variant, nBMP2, is expressed in mouse hippocampus and impacts memory

Abstract

The novel nuclear protein nBMP2 is synthesized from the BMP2 gene by translational initiation at an alternative start codon. We generated a targeted mutant mouse, nBmp2NLStm, in which the nuclear localization signal (NLS) was inactivated to prevent nuclear translocation of nBMP2 while still allowing the normal synthesis and secretion of the BMP2 growth factor. These mice exhibit abnormal muscle function due to defective Ca2+ transport in skeletal muscle. We hypothesized that neurological function, which also depends on intracellular Ca2+ transport, could be affected by the loss of nBMP2. Age-matched nBmp2NLStm and wild type mice were analyzed by immunohistochemistry, behavioral tests, and electrophysiology to assess nBMP2 expression and neurological function. Immunohistochemical staining of the hippocampus detected nBMP2 in the nuclei of CA1 neurons in wild type but not mutant mice, consistent with nBMP2 playing a role in the hippocampus. Mutant mice showed deficits in the novel object recognition task, suggesting hippocampal dysfunction. Electrophysiology experiments showed that long-term potentiation (LTP) in the hippocampus, which is dependent on intracellular Ca2+ transport and is thought to be the cellular equivalent of learning and memory, was impaired. Together, these results suggest that nBMP2 in the hippocampus impacts memory formation.

The nuclear variant of bone morphogenetic protein 2 (nBMP2) is expressed in macrophages and alters calcium response

“…Alternatively, it may be that the effects of nBMP2 deficiency in the nucleus are simply cumulative, causing a Ca 2+ -handling phenotype that becomes progressively more severe as cells differentiate and mature. A progressive phenotype is consistent with our previously reported observation that hippocampal long-term potentiation (LTP) was normal in 3-week-old nBmp2NLS tm mutant mice but deficient in 3-month-old mice 3 . Progressive impairment of intracellular Ca 2+ response has received attention recently as a potential mechanism for both brain and muscle aging 36–38 , suggesting that nBMP2 dysfunction could contribute to premature aging or aging-related diseases.…”

“…Previously, we demonstrated that deficiency of nBMP2 in the nucleus impairs secondary immune response as evidenced by diminished spleen enlargement, poor clearance of S. aureus from the bloodstream, and increased mortality after secondary infection 11 . We have also shown that deficiency of nBMP2 in myonuclei is correlated with slowed skeletal muscle relaxation after contraction, and deficiency of nBMP2 in the nuclei of hippocampal neurons is correlated with learning/memory deficits 2,3 . Each of these phenotypes is consistent with deficiencies in intracellular Ca 2+ transport, but until now, no direct measurements of intracellular Ca 2+ have been performed in cells from nBmp2NLS tm mutant mice.…”

“…Instead, nBMP2 is translated in the cytoplasm and translocated to the nucleus by means of an embedded bipartite nuclear localization signal (NLS) 1 . Using immunohistochemistry, we have detected nBMP2 in skeletal muscle nuclei and in the nuclei of CA1 neurons in the hippocampus 2,3 .…”

“…Consistent with impaired intracellular Ca 2+ transport, sarco/endoplasmic reticulum Ca 2+ ATPase (SERCA) activity is decreased in skeletal muscle 2 . The mutant mice also lack nBMP2 in CA1 hippocampal neurons, and electrophysiological studies revealed reduced long-term potentiation (LTP) in the hippocampus 3 . LTP is dependent on intracellular Ca 2+ transport and is thought to be the cellular equivalent of learning and memory 4–6 .…”

“…LTP is dependent on intracellular Ca 2+ transport and is thought to be the cellular equivalent of learning and memory 4–6 . Behavioral tests revealed that the nBMP2 mutant mice have impaired object recognition memory 3 .…”