Previous work demonstrated a role for nonmuscle myosin heavy chain (NMHC) II-B during mouse brain development. Mice carrying a point mutation in NMHC II-B (R709C) demonstrated decreased migration of cerebellar granule cells, pontine neurons and facial neurons. Due to the presence of the Neo-r cassette in an intron, these mice expressed decreased quantities of the mutant protein (25% of the amount of protein expressed by the wild-type mouse). Removing this cassette by crossing hypomorphic mice with mice expressing Cre-recombinase restored normal expression of the mutant allele and also generated a new phenotype. These mice (B-C/B-C) developed focal disruptions of the cortical basement membrane as early as E12. At the disrupted areas, clusters of a neural cell mass abnormally protruded into the marginal zone between the neuroepithelium and the pia-meninges, resembling type II cobblestone lissencephaly. Interestingly, these abnormalities were not seen in NMHC II-B ablated mice, indicating that these defects were not due to a loss-of-function of NMHC II-B. Since the defect was only seen in homozygous mutant mice, the mutant NMHC II-B could not be affecting the normal function of wild-type II-B. This suggests that mutant NMHC II-B interfered with the function of other members of the NMHC II family. Immunostaining using specific antibodies demonstrated that, whereas NMHC II-A and II-B were expressed, NMHC II-C was not expressed to a significant extent in the area around the basement membrane. Moreover, no NMHC II-C was found in meningeal fibroblast cells, which secrete a major component of cortical basement membrane. We postulate that the R709C mutation in NMHC II-B results in focal disruption of the cortical basement membrane because of its dominant negative effect on NMHC II-A

Agency
National Institute of Health (NIH)
Institute
National Heart, Lung, and Blood Institute (NHLBI)
Type
Intramural Research (Z01)
Project #
1Z01HL004228-10
Application #
6966994
Study Section
(LMC)
Project Start
Project End
Budget Start
Budget End
Support Year
10
Fiscal Year
2004
Total Cost
Indirect Cost
Name
U.S. National Heart Lung and Blood Inst
Department
Type
DUNS #
City
State
Country
United States
Zip Code
Zhang, Yingfan; Liu, Chengyu; Adelstein, Robert S et al. (2018) Replacing nonmuscle myosin 2A with myosin 2C1 permits gastrulation but not placenta vascular development in mice. Mol Biol Cell 29:2326-2335
Ma, Xuefei; Sung, Derek C; Yang, Yanqin et al. (2017) Nonmuscle myosin IIB regulates epicardial integrity and epicardium-derived mesenchymal cell maturation. J Cell Sci 130:2696-2706
He, Yin; Beatty, Alexander; Han, Xuemei et al. (2012) Nonmuscle myosin IIB links cytoskeleton to IRE1? signaling during ER stress. Dev Cell 23:1141-52
Yamamoto, Norio; Okano, Takayuki; Ma, Xuefei et al. (2009) Myosin II regulates extension, growth and patterning in the mammalian cochlear duct. Development 136:1977-86
Ma, Xuefei; Bao, Jianjun; Adelstein, Robert S (2007) Loss of cell adhesion causes hydrocephalus in nonmuscle myosin II-B-ablated and mutated mice. Mol Biol Cell 18:2305-12
Ma, Xuefei; Kawamoto, Sachiyo; Uribe, Jorge et al. (2006) Function of the neuron-specific alternatively spliced isoforms of nonmuscle myosin II-B during mouse brain development. Mol Biol Cell 17:2138-49
Ma, Xuefei; Kawamoto, Sachiyo; Hara, Yoshinobu et al. (2004) A point mutation in the motor domain of nonmuscle myosin II-B impairs migration of distinct groups of neurons. Mol Biol Cell 15:2568-79
Lo, Chun-Min; Buxton, Denis B; Chua, Gregory C H et al. (2004) Nonmuscle myosin IIb is involved in the guidance of fibroblast migration. Mol Biol Cell 15:982-9
Tullio, A N; Bridgman, P C; Tresser, N J et al. (2001) Structural abnormalities develop in the brain after ablation of the gene encoding nonmuscle myosin II-B heavy chain. J Comp Neurol 433:62-74