A Novel Bone Morphogenetic Protein 2 Mutant Mouse, , Displays Impaired Intracellular Handling in Skeletal Muscle

Bridgewater, Laura C.; Mayo, Jaime L.; Evanson, Bradley G.; Whitt, Megan E.; Dean, Spencer A.; Yates, Joshua D.; Holden, Devin N.; Schmidt, Alina; Fox, Christopher L.; Dhunghel, Saroj; Steed, Kevin; Adam, Michael M.; Nichols, Caitlin A.; Loganathan, Sampath K.; Barrow, Jeffery R.; Hancock, Chad R.

doi:10.1155/2013/125492

Cited by 4 publications

(21 citation statements)

References 39 publications

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“…This data complements and expands our previous report that nBMP2 is expressed in skeletal muscle and that the nBmp2NLS tm mouse shows anomalies in skeletal muscle contractions that suggest dysregulation of intracellular Ca 2+ transport9. The importance of Ca 2+ transport in hippocampal-based learning and memory formation is well documented3334353637.…”

Section: Discussionsupporting

confidence: 89%

“…The nBmp2NLS tm mice were constructed on a Bl6/129 background, as described9. The homozygous wild type and mutant mice used in this study were obtained by breeding heterozygous males and females.…”

Section: Methodsmentioning

confidence: 99%

“…But whereas wild type mice show expression of nBMP2 in the nuclei of skeletal muscle myotubes, mutant mice do not. The absence of nBMP2 in skeletal muscle nuclei results in slowed relaxation of skeletal muscle after stimulated contractions, consistent with impaired re-uptake of Ca 2+ from the cytoplasm into the sarcoplasmic reticulum at the end of each contraction cycle9. Homozygous nBmp2NLS tm mice also show an impaired secondary immune response to systemic bacterial infection, which might similarly arise from defective intracellular Ca 2+ signaling during the process of immune cell activation or differentiation11.…”

mentioning

confidence: 91%

“…The targeted mutation disrupts nuclear localization of nBMP2 while retaining normal secreted BMP2 growth factor synthesis and function910. Homozygous nBmp2NLS tm mice are normal in size and morphology.…”

mentioning

confidence: 99%

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

Cordner

Friend

Mayo

et al. 2017

Sci Rep

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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.

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Section: Discussionsupporting

confidence: 89%

Section: Methodsmentioning

confidence: 99%

mentioning

confidence: 91%

mentioning

confidence: 99%

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

Cordner

Friend

Mayo

et al. 2017

Sci Rep

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“…To distinguish the functions of secreted BMP2 from nBMP2, we generated a mouse strain containing a targeted mutation in which the conventional growth factor BMP2 is secreted and signals normally, but nBMP2 is excluded from the nucleus by means of a three-amino-acid substitution in the nuclear localization signal [ 2 ]. The resulting nBmp2NLS tm mice are normal in size, morphology, and fertility, but males exhibit slowed relaxation of skeletal muscles after stimulated contractions.…”

Section: Introductionmentioning

confidence: 99%

Targeted Mutation of Nuclear Bone Morphogenetic Protein 2 Impairs Secondary Immune Response in a Mouse Model

Olsen

Goar

Nichols

et al. 2015

BioMed Research International

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We recently identified a nuclear variant of the BMP2 growth factor, called nBMP2. In an effort to understand the function of this variant protein, we generated a mouse line in which BMP2 is expressed and functions normally, but nBMP2 is excluded from the nucleus. This novel mutation allows the study of nBMP2 without compromising BMP2 function. To determine whether nBMP2 plays a role in immune function, we performed a series of experiments in which we compared mouse survival, organ weights, immune cells numbers, and bacterial load in wild type and nBmp2NLStm mice following primary and secondary challenges with Staphylococcus aureus. Following primary challenge with S. aureus, wild type and nBmp2NLStm mice showed no differences in survival or bacterial load and generated similar numbers and types of leukocytes, although mutant spleens were smaller than wild type. Secondary bacterial challenge with S. aureus, however, produced differences in survival, with increased mortality seen in nBmp2NLStm mice. This increased mortality corresponded to higher levels of bacteremia in nBmp2NLStm mice and to a reduced enlargement of mutant spleens in response to the secondary infection. Together, these results suggest that the recently described nuclear variant of BMP2 is necessary for efficient secondary immune responses.

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Histomorphometry of ectopic mineralization using undecalcified frozen bone sections

Fujihara

Chiba

Nakagawa

et al. 2018

Microscopy Res & Technique

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To investigate the correlation between mineral formation and enhanced expressions of some proteins using undecalcified frozen bone sections. Histological studies have revealed that some proteins, such as BMP2, BMPR1A, and Connexin 43, are expressed in and around sites of ectopic ossification. However, the relationship between the expressed proteins considered to be associated with the ossification and mineral formation in vivo is not clear. Ectonucleotide pyrophosphatase phosphodiesterase 1 (ENPP1)-mutant spinal hyperostotic TWY mice and ICR mice as controls were euthanized after calcein labeling, and undecalcified frozen sections were obtained from the middle thoracic spine. Intervertebral disc areas were examined histologically and by measuring calcein-labeled areas and areas showing immunoreactivity for BMP2, BMPR1A, and Connexin 43. Calcein-labeled areas, indicating mineralization in the ectopic mineralization sites, were significantly larger in the mutant mice than in controls. The expression of Connexin 43 was elevated in the annulus fibrosus. Increases in the calcein-labeled areas was not correlated with increases in the areas showing immunoreactivity for Connexin 43 in the annulus fibrosus. There was no statistical correlation between enhanced immunohistochemical expression and elevated calcein-labeled areas. By applying the morphometrical analysis method using undecalcified frozen sections to ENPP1-mutant mice, quantitative evaluation of the mineralization and proteins expressed in the surrounding area in the same animal became possible. K E Y W O R D S BMP2, BMPR1A, Connexin 43, ENPP1, histomorphometry, mineralization, ossification of the posterior longitudinal ligament, undecalcified frozen section

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A Novel Bone Morphogenetic Protein 2 Mutant Mouse, , Displays Impaired Intracellular Handling in Skeletal Muscle

Cited by 4 publications

References 39 publications

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

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

Targeted Mutation of Nuclear Bone Morphogenetic Protein 2 Impairs Secondary Immune Response in a Mouse Model

Histomorphometry of ectopic mineralization using undecalcified frozen bone sections

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