Myosin-X knockout is semi-lethal and demonstrates that myosin-X functions in neural tube closure, pigmentation, hyaloid vasculature regression, and filopodia formation

Abstract

Myosin-X (Myo10) is an unconventional myosin best known for its striking localization to the tips of filopodia. Despite the broad expression of Myo10 in vertebrate tissues, its functions at the organismal level remain largely unknown. We report here the generation of KO-first (Myo10 tm1a/tm1a), floxed (Myo10 tm1c/tm1c), and KO mice (Myo10 tm1d/tm1d). Complete knockout of Myo10 is semi-lethal, with over half of homozygous KO embryos exhibiting exencephaly, a severe defect in neural tube closure. All Myo10 KO mice that survive birth exhibit a white belly spot, all have persistent fetal vasculature in the eye, and ~50% have webbed digits. Myo10 KO mice that survive birth can breed and produce litters of KO embryos, demonstrating that Myo10 is not absolutely essential for mitosis, meiosis, adult survival, or fertility. KO-first mice and an independent spontaneous deletion (Myo10 m1J/m1J) exhibit the same core phenotypes. During retinal angiogenesis, KO mice exhibit a ~50% decrease in endothelial filopodia, demonstrating that Myo10 is required to form normal numbers of filopodia in vivo. The Myo10 mice generated here demonstrate that Myo10 has important functions in mammalian development and provide key tools for defining the functions of Myo10 in vivo.

Genetic investigation of 93 families with microphthalmia or posterior microphthalmos

“…More specifically, a spontaneous Myo10 recessive mutation (Myo10 m1J /Myo10 m1J ) in mice led to the presence of anophthalmia in 1/14 and 3/14 with severe microphthalmia in addition to iris coloboma as well as corneal opacity and persistence of the hyaloid vascular system, decreased body size and tail pigmentation and syndactyly. 61 Similarly, a targeted null knockout mouse also exhibited a strong eye phenotype consisting of abnormal corneal morphology, corneal opacity, fused cornea and lens, abnormal retinal morphology, impaired pupillary reflex as well as persistence of the hyaloid vascular system. 12 The presence of a dramatic eye phenotype in both mouse mutants strongly supports a role MYO10 plays during embryonic eye development, as we show in our patient.…”

Lack of Myosin X Enhances Osteoclastogenesis and Increases Cell Surface Unc5b in Osteoclast-Lineage Cells

“…Generation of osteoblast‐selective Myo10 cko mice will contribute to clarify the cell‐autonomous role of Myo10 in bone formation. A previous study indicates that Myo10 has multiple forms and complete KO Myo10 is semi‐lethal . The Myo10 m/m mouse characterized here was not a null, but a hypomorphic allele, with loss of Myo10 function.…”

“…A previous study indicates that Myo10 has multiple forms and complete KO Myo10 is semi-lethal. (28) The Myo10 m/m mouse characterized here was not a null, but a hypomorphic allele, with loss of Myo10 function. As shown in Fig.…”

“…Myo10 is expressed in both OB and OC lineage cells. By micro-computed tomography (mCT) and bone histomorphometric analyses of a Myo10 loss of function mutant mouse line (named as Myo10 m/m ; also called Myo10 tm11a/tmla in previous report (28) ), we observed osteoporotic deficits in Myo10 m/m mice. The osteoporotic deficits appear to be due in large to the increased OC differentiation and bone resorption, because no significant changes were detected in bone formation.…”

Three-dimensional organization of transzonal projections and other cytoplasmic extensions in mouse ovarian follicles

“…They also reveal the presence of cytoplasmic projections among granulosa cells within the follicle. As in other tissues and systems, these projections may be essential for cell communication during normal development and function (Ramirez-Weber and Kornberg, 1999; Inaba et al, 2015; Heimsath et al, 2017).…”