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Abnormalities in the cerebellar Purkinje cell development in B2 insert-ablated mice. (A) H&E staining of a sagittal section of adult B2 insert-ablated mouse cerebellum shows misplacement of some of the cerebellar Purkinje cells (arrows) from the Purkinje cell layer (PL) to the molecular layer. (B) Immunohistochemical staining of a sagittal section of B2-ablated mouse cerebellum using antibodies against calbindin shows an abnormal orientation of the dendritic tree of some Purkinje cells (arrow) compared with their normal perpendicular orientation (arrowhead). (C and D) Immunofluorescence confocal images using antibodies against calbindin show a decreased number of dendritic branches and spines (arrows) in the Purkinje cells of a B2 insert- ablated mouse (D) compared with a wild-type littermate (C).
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We report that the alternatively spliced isoforms of nonmuscle myosin heavy chain II-B (NHMC II-B) play distinct roles during mouse brain development. The B1-inserted isoform of NMHC II-B, which contains an insert of 10 amino acids near the ATP-binding region (loop 1) of the myosin heavy chain, is involved in normal migration of facial neurons. In...
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Context 1
... B B2N /B B2N mice showed ab- normalities in the development of the cerebellar Purkinje cells. The cell bodies of a small percentage of the Purkinje cells were consistently dissociated from the cerebellar Purkinje cell layer and were ectopically located in the mo- lecular layer ( Figure 6A, arrows). Immunohistochemical staining of parasagittal sections of the adult mouse cerebel- lum using an antibody against calbindin, which specifically stains Purkinje cells, revealed an abnormal orientation of the dendritic tree of a small number of the B B2N /B B2N Pur- kinje cells ( Figure 6B, arrow). ...
Context 2
... cell bodies of a small percentage of the Purkinje cells were consistently dissociated from the cerebellar Purkinje cell layer and were ectopically located in the mo- lecular layer ( Figure 6A, arrows). Immunohistochemical staining of parasagittal sections of the adult mouse cerebel- lum using an antibody against calbindin, which specifically stains Purkinje cells, revealed an abnormal orientation of the dendritic tree of a small number of the B B2N /B B2N Pur- kinje cells ( Figure 6B, arrow). Normally, Purkinje cells are oriented perpendicularly to the surface of the cerebellar cortex ( Figure 6B, arrowhead). ...
Context 3
... staining of parasagittal sections of the adult mouse cerebel- lum using an antibody against calbindin, which specifically stains Purkinje cells, revealed an abnormal orientation of the dendritic tree of a small number of the B B2N /B B2N Pur- kinje cells ( Figure 6B, arrow). Normally, Purkinje cells are oriented perpendicularly to the surface of the cerebellar cortex ( Figure 6B, arrowhead). Importantly, immunofluores- cence microscopy of calbindin staining further demon- strated that almost all of the B B2N /B B2N Purkinje cells showed a marked decrease in branches and dendritic spines ( Figure 6D) compared with the wild-type cells ( Figure 6C). ...
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... Purkinje cells are oriented perpendicularly to the surface of the cerebellar cortex ( Figure 6B, arrowhead). Importantly, immunofluores- cence microscopy of calbindin staining further demon- strated that almost all of the B B2N /B B2N Purkinje cells showed a marked decrease in branches and dendritic spines ( Figure 6D) compared with the wild-type cells ( Figure 6C). Branches were counted as the number of dendritic branches crossing lines perpendicular to the orientation of the den- dritic arbors in confocal images stained with calbindin. ...
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... Purkinje cells are oriented perpendicularly to the surface of the cerebellar cortex ( Figure 6B, arrowhead). Importantly, immunofluores- cence microscopy of calbindin staining further demon- strated that almost all of the B B2N /B B2N Purkinje cells showed a marked decrease in branches and dendritic spines ( Figure 6D) compared with the wild-type cells ( Figure 6C). Branches were counted as the number of dendritic branches crossing lines perpendicular to the orientation of the den- dritic arbors in confocal images stained with calbindin. ...
Context 6
... addition, the punctate distri- bution and colocalization of B2-inserted NMHC II-B with actin, both of which are enriched in the dendritic spines (Matus, 2000, for actin localization), indicates a possible role in spine formation. These ideas were further supported by the finding that deletion of the B2 insert caused a reduction in the number of spines and dendritic branches associated with Purkinje cells ( Figure 6D). Consistent with these ideas, the importance of NHMC II-B in the regulation of lamel- lopodia and filapodia formation was previously demon- strated in studies on NMHC II-B ablated neuronal growth cones ). ...
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Histochemical analysis of balloon-injured rat carotid arteries revealed a coordinated expression of nonmuscle myosin heavy chain-A and -B (NM-A and NM-B) in response to injury. Expression of these nonmuscle myosin forms shifts from the media to the adventitia and intima. In contrast, expression of smooth muscle myosin heavy chain-1 (SM-1) within th...
Citations
... Insertion of 10 or 16 aa at the loop 1 of NMHC IIB (NM IIB1a or -B1b, respectively) is neuronal tissue-specific and it makes up most of the NMHC IIB mRNA in the human cerebrum and retina (13). The expression of these isoforms correlates with neuronal cell differentiation, facial neuron migration, and inhibition of cell division (13,14). The 10 aa inserted isoform, NM IIB1a, shows only a small increase in the Mg 2+ -ATPase activity and the in vitro motility compared to the non-inserted isoform (15). ...
... On the other hand, insertion of 21 aa or 33 aa at loop 2 of NMHC IIB and IIC, respectively, is neuronal tissue specific (9,16). Kim et al. (16) concluded that NM IIB2 (21 aa) lacks enzymatic activity but plays an important role in cerebellar development, such as, Purkinje cell localization and maturation, dendrites and the dendritic spine formation (14). A further study using full length protein concluded that although the IIB2 has an order of magnitude lower actin activated ATPase than the non-inserted variant, it nonetheless has a measurable activity (11). ...
... Having the similar low motor activity of NM IIA2, we can hypothesize that NM IIA2 may have roles in cellular processes that depend more on the structural (filament-forming and actin anchoring) properties than the motor activities. NM IIB2 has been shown to be involved in cerebellar development, particularly with respect to Purkinje cell localization and maturation and controlling the number of dendritic spines and branches associated with Purkinje cells (14). Although we confirmed the brain-specific presence of a novel alternatively spliced isoform NM IIA2, we were not able to detect NMHC IIA2 mRNA in neuronal cell lines such as Neuro 2A, SH-SY5Y, PC-12, suggesting that NM IIA2 is present in very limited abundance or in some specific cell types in the brain, which have not been tested yet. ...
Recent genomic studies reported 90-95% of human genes can undergo alternative splicing, by which multiple isoforms of proteins are synthesized. However, the functional consequences of most of the isoforms are largely unknown. Here, we report a novel alternatively spliced isoform of nonmuscle myosin IIA (NM IIA), called NM IIA2, which is generated by the inclusion of 21 amino acids near the actin binding region (loop 2) of the head domain of heavy chains. Expression of NM IIA2 is found exclusively in the brain tissue, where it reaches a maximum level at 24h during the circadian rhythm. The actin-dependent Mg2+-ATPase activity and in vitro motility assays reveal that NM IIA2 lacks its motor activities but localizes with actin filaments in cells. Interestingly, NM IIA2 can also make heterofilaments with NM IIA0 (non-inserted isoform of NM IIA) and can retard the in vitro motility of NM IIA, when the two are mixed. Altogether, our findings provide the functional importance of a previously unknown alternatively spliced isoform, NM IIA2, and its potential physiological role in regulating NM IIA activity in the brain.
... 9 Our future studies will explore the distinct roles of MYH10 isoforms in different cellular contexts. 40 Overall, these data provide evidence for a unifying autosomal dominant disorder caused by heterozygous variants in the MYH10 gene. Future directions will include direct analysis of patient samples, CAS9-mediated variant knockin cellular models, and targeted mouse knockin models to further delineate the biochemical, cellular, and phenotypic effect of the identified variants that will likely reveal both overlapping and distinct mechanisms of action in a tissue-specific manner. ...
Purpose
Nonmuscle myosin II complexes are master regulators of actin dynamics that play essential roles during embryogenesis with vertebrates possessing 3 nonmuscle myosin II heavy chain genes, MYH9, MYH10, and MYH14. As opposed to MYH9 and MYH14, no recognizable disorder has been associated with MYH10. We sought to define the clinical characteristics and molecular mechanism of a novel autosomal dominant disorder related to MYH10.
Methods
An international collaboration identified the patient cohort. CAS9-mediated knockout cell models were used to explore the mechanism of disease pathogenesis.
Results
We identified a cohort of 16 individuals with heterozygous MYH10 variants presenting with a broad spectrum of neurodevelopmental disorders and variable congenital anomalies that affect most organ systems and were recapitulated in animal models of altered MYH10 activity. Variants were typically de novo missense changes with clustering observed in the motor domain. MYH10 knockout cells showed defects in primary ciliogenesis and reduced ciliary length with impaired Hedgehog signaling. MYH10 variant overexpression produced a dominant-negative effect on ciliary length.
Conclusion
These data presented a novel genetic cause of isolated and syndromic neurodevelopmental disorders related to heterozygous variants in the MYH10 gene with implications for disrupted primary cilia length control and altered Hedgehog signaling in disease pathogenesis.
... Consistent with this paradigm, myosin 2B is enriched along with F-actin in spines, and attenuating the myosin's function in developing neurons either pharmacologically or by knockdown results in a strong block in spine maturation. [45][46][47][48][49][50][51][52][53][54] Moreover, blocking myosin 2B function in fully developed neurons shows that it also plays a critical role in the activity-dependent changes in spine actin morphology underlying learning and memory. 48,50,[52][53][54] While myosin 2B is present in dendritic filopodia as well as in mature spines, 22 its function in mature spines has been studied most. ...
... 52 Interestingly, Purkinje neurons express an alternatively spliced version of myosin 2B known as myosin 2B-B2 in addition to regular myosin 2B. 47 Mice lacking this splice variant exhibit aberrant Purkinje neuron development (reduced numbers of dendritic spines and branches) and impaired motor coordination. 47 The focus of this study is on the function of the myosin 2-like protein myosin 18Aα, 55,56 one of three alternatively spliced isoforms generated from the mouse M18A gene. ...
... 47 Mice lacking this splice variant exhibit aberrant Purkinje neuron development (reduced numbers of dendritic spines and branches) and impaired motor coordination. 47 The focus of this study is on the function of the myosin 2-like protein myosin 18Aα, 55,56 one of three alternatively spliced isoforms generated from the mouse M18A gene. Like myosin 2, all three myosin 18A isoforms possess a globular head domain followed by a rod-like coiled-coil tail domain. ...
Myosin 18Aα is a myosin 2‐like protein containing unique N‐ and C‐terminal protein interaction domains that co‐assembles with myosin 2. One protein known to bind to myosin 18Aα is β‐Pix, a guanine nucleotide exchange factor (GEF) for Rac1 and Cdc42 that has been shown to promote dendritic spine maturation by activating the assembly of actin and myosin filaments in spines. Here, we show that myosin 18A⍺ concentrates in the spines of cerebellar Purkinje neurons via co‐assembly with myosin 2 and through an actin binding site in its N‐terminal extension. miRNA‐mediated knockdown of myosin 18A⍺ results in a significant defect in spine maturation that is rescued by an RNAi‐immune version of myosin 18A⍺. Importantly, β‐Pix co‐localizes with myosin 18A⍺ in spines, and its spine localization is lost upon myosin 18A⍺ knockdown or when its myosin 18A⍺ binding site is deleted. Finally, we show that the spines of myosin 18A⍺ knockdown Purkinje neurons contain significantly less F‐actin and myosin 2. Together, these data argue that mixed filaments of myosin 2 and myosin 18A⍺ form a complex with β‐Pix in Purkinje neuron spines that promotes spine maturation by enhancing the assembly of actin and myosin filaments downstream of β‐Pix's GEF activity.
... Accordingly, the non-contractile NMIIB R709C mutant leads to persistence of filopodia-like spines and reduces postsynaptic density (PSD) maturation [118]. Furthermore, mice lacking the NMII B2 alternative splice variant, which binds to actin but lacks actin-activated ATPase activity and motility in vitro [120], show mislocalization and reduction of dendritic spines and branches of Purkinje cells, leading to impaired motor coordination [121]. ...
Myosins are motor proteins that use chemical energy to produce mechanical forces driving actin cytoskeletal dynamics. In the brain, the conventional non-muscle myosin II (NMII) regulates actin filament cytoskeletal assembly and contractile forces during structural remodeling of axons and dendrites, contributing to morphology, polarization, and migration of neurons during brain development. NMII isoforms also participate in neurotransmission and synaptic plasticity by driving actin cytoskeletal dynamics during synaptic vesicle release and retrieval, and formation, maturation, and remodeling of dendritic spines. NMIIs are expressed differentially in cerebral non-neuronal cells, such as microglia, astrocytes, and endothelial cells, wherein they play key functions in inflammation, myelination, and repair. Besides major efforts to understand the physiological functions and regulatory mechanisms of NMIIs in the nervous system, their contributions to brain pathologies are still largely unclear. Nonetheless, genetic mutations or deregulation of NMII and its regulatory effectors are linked to autism, schizophrenia, intellectual disability, and neurodegeneration, indicating non-conventional roles of NMIIs in cellular mechanisms underlying neurodevelopmental and neurodegenerative disorders. Here, we summarize the emerging biological roles of NMIIs in the brain, and discuss how actomyosin signaling contributes to dysfunction of neurons and glial cells in the context of neurological disorders. This knowledge is relevant for a deep understanding of NMIIs on the pathogenesis and therapeutics of neuropsychiatric and neurodegenerative diseases.
... The contractile activity of these bipolar filaments is thought to drive the shortening of immature spines during spine maturation, the constriction of the spine neck, the tip-to-base flow of a dynamic spine actin pool, the cross-linking of a stable spine actin pool, and possibly global spine actin dynamics by catalyzing actin filament turnover downstream of myosin-dependent actin filament breakage (Ozkan et al., 2015). Interestingly, Purkinje neurons express an alternatively spliced version of myosin 2B known as myosin 2B-B2 in addition to regular myosin 2B (Ma et al., 2006). Mice lacking this splice variant exhibit aberrant Purkinje neuron development (reduced numbers of dendritic spines and branches) and impaired motor coordination (Ma et al., 2006). ...
... Interestingly, Purkinje neurons express an alternatively spliced version of myosin 2B known as myosin 2B-B2 in addition to regular myosin 2B (Ma et al., 2006). Mice lacking this splice variant exhibit aberrant Purkinje neuron development (reduced numbers of dendritic spines and branches) and impaired motor coordination (Ma et al., 2006). ...
... All oligonucleotides used in this study were purchased from Eurofins Genomics at 50 nM scale and purified by standard desalting. Table 1 shows the oligonucleotides used to generate the pL7-based (Wagner, McCroskery and Hammer, 2011), Purkinje neuron-specific expression plasmids for myosin 18Aα, myosin 18Aβ, myosin 2B, and b-Pix using the following DNA templates: mouse myosin 18A (Riken clone F730020C19), mouse myosin 2B-B2 (Ma et al., 2006), and mouse b-Pix (Mammalian Gene Collection clone MMM1013-202702676). DNA fragments containing 21 base pair overhangs homologous to the vector backbone were generated by PCR using Phusion High-Fidelity DNA polymerase (NEB, M0530), purified, and inserted into Bgl II/Sal I-linearized pL7 mGFP or pL7 mCherry (Wagner, McCroskery and Hammer, 2011) using an In-Fusion cloning kit (Takara, 638920). ...
Dendritic spines are signaling microcompartments that serve as the primary site of synapse formation in neurons. Actin assembly and myosin 2 contractility play major roles in the maturation of spines from filopodial precursors, as well as in the subsequent, activity-dependent changes in spine morphology that underly learning and memory. Myosin 18A is a myosin 2-like protein conserved from flies to man that lacks motor activity, is sub-stochiometric to myosin 2, and co-assembles with myosin 2 to make mixed filaments. Myosin 18A is alternatively spliced to create multiple isoforms that contain unique N- and C-terminal extensions harboring both recognizable and uncharacterized protein: protein interaction domains. These observations suggest that myosin 18A serves to recruit proteins to mixed filaments of myosin 2 and myosin 18A. One protein known to bind to myosin 18A is β-Pix, a guanine nucleotide exchange factor (GEF) for Rac1 and Cdc42. Notably, β-Pix has been shown to promote spine maturation by activating both Arp2/3 complex-dependent branched actin filament assembly and myosin 2 contractility within spines. Here we show that myosin 18Aα is expressed in cerebellar Purkinje neurons and concentrates in spines along with myosin 2 and F-actin. Myosin 18Aα is targeted to spines by co-assembling with myosin 2 and by an actin binding site present in its N-terminal extension. miRNA-mediated knockdown of myosin 18Aα results in a significant defect in spine maturation that is rescued by an RNAi-immune version of myosin 18Aα. Importantly, β-Pix co-localizes with myosin 18Aα in spines, and its spine localization is lost upon myosin 18A&α knockdown or when its myosin 18Aα binding site is deleted. Finally, we show that the spines of myosin 18Aα knockdown Purkinje neurons contain significantly less F-actin and myosin 2. Together, these data demonstrate that mixed filaments of myosin 2 and myosin 18Aα form a complex with β-Pix in Purkinje neuron spines that promotes spine maturation by enhancing the assembly of actin and myosin filaments downstream of β-Pixs GEF activity.
... 273 with ACTB and ACTG1, two BWCFF genes. 275,276 Therefore, functional analyses using patient cells and zebrafish models were performed to explore the phenotypes due to MYH10 loss-of-function mutations, showing its requirement for eye development in association with the actin ACTB and ACTG1 ...
... The NMHC IIB myosin encoded by the MYH10 gene is preferentially localized to the rear of the cell in migratory cells.290 In mice, MYH10 is specifically enriched in neuronal tissue during mouse embryonic development and is critical for neuronal cell migration and for reorganization of the actin cytoskeleton.275,276 Two de novo heterozygous variants of unknown significance in MYH10 have been previously mentioned in patients presenting with a severe neurodevelopmental phenotype and brain anomalies but no further studies were performed leaving their pathogenic role uncertain.291,292 ...
Worldwide, there are more than 7,000 rare diseases for which 80 % are of genetic origin and for which the gene or genes are not yet all known. Although the interest in rare diseases has increased in recent years, there is a lack of therapeutic strategies for most of them. During my thesis, I focused on the identification and validation of new genes associated with neurosensory and neurodevelopmental diseases. The strategy I used during my thesis to identify new disease-causing genes is based primarily on the analysis of high-throughput sequencing data from patients, the confirmation of variants by Sanger sequencing, and the performance of functional experiments using patient cells and the zebrafish model to proof the pathogenicity of the novel gene mutations. Overall, I contributed to the identification of three novel disease genes associated with neurodevelopmental and neurosensory diseases. The results obtained in this thesis improve the understanding of the pathophysiology of these diseases and may help to find new therapeutic targets.
... PNs were identified using anti-Calbindin D28K antibody (guinea pig, 1 to 500; Synaptic Systems, 214004). Depending on the experiment, cultures were also stained with the following primary antibodies at the indicated dilutions: anti-IP3R1 (mouse, 1 to 200; Santa Cruz, sc-271197), anti-AHCYL1 (IRBIT) (mouse, 1 to 200; Neobiolab, A7773), anti-PLCβ4 (mouse, 1 to 500; Santa Cruz sc-166131), anti-PSD93 (mouse, 1 to 200; Millipore, MABN497), or anti-myosin IIB-B2 (rabbit, 1 to 200; [43]) in 200 μL of IF blocking solution for 45 min at room temperature. Following three 10-min washes in PBS, samples were incubated at room temperature with 1 to 500 dilutions of the appropriate labeled secondary antibody (Alexa Fluor 546 goat anti-guinea pig, Thermo Fisher, A12074; Alexa Fluor 488 goat anti-mouse, Thermo Fisher, A11001; Alexa Fluor 488 goat anti-rabbit, Thermo Fisher, A11008). ...
... As with mature PNs in tissue [78][79][80] and in primary culture (Fig. S5), the dendritic spines of mESC-derived PNs stain robustly for the PN-specific postsynaptic density protein PSD93 [10,78,87,88] (Fig. 4A1-A4) and for the PN-specific isoform of phospholipase C, PLCβ4 [79] (Fig. 4B1-B4). Also, like PNs in tissue and primary culture (Fig. S5), mESC-derived PNs stain robustly at the base of their spines for a PN-specific splice isoform of nonmuscle myosin IIB (nonmuscle myosin IIB-B2; [43,89]) ( Fig. 4C1-C4). Finally, like PNs in tissue [90][91][92] and primary culture [10][11][12] (Fig. S5), essentially every spine in mESCderived PNs contains smooth endoplasmic reticulum (SER), as evidenced by staining for IP3 receptor 1 (IP3R1) (Fig. 4D1-D4) and for the IP3R1-associated protein IRBIT [93] (Fig. 4E1-E4). ...
... Second, the cells stain for six markers used previously by us and others to identify PNs, with each localizing to its correct cellular compartment (Figs. 3, 4, and S5). While there may be no marker that is absolutely PN specific, our use of six markers that are specific to PNs in mixed primary cerebellar cultures ( Fig. S5 and [43,[78][79][80][89][90][91][92]) exceeds what is commonly provided as evidence for the creation of bona fide PNs from stem cells (see for example Watson et al. [65], where only two markers were used to argue that bona fide PNs had been generated from IPSCs). Third, the cells express proteins under the control of the PN-specific promoter Pcp2/L7 (Fig. S6). ...
While mixed primary cerebellar cultures prepared from embryonic tissue have proven valuable for dissecting structure–function relationships in cerebellar Purkinje neurons (PNs), this technique is technically challenging and often yields few cells. Recently, mouse embryonic stem cells (mESCs) have been successfully differentiated into PNs, although the published methods are very challenging as well. The focus of this study was to simplify the differentiation of mESCs into PNs. Using a recently described neural differentiation media, we generate monolayers of neural progenitor cells from mESCs and differentiate them into PN precursors using specific extrinsic factors. These PN precursors are then differentiated into mature PNs by co-culturing them with granule neuron (GN) precursors also derived from neural progenitors using different extrinsic factors. The morphology of mESC-derived PNs is indistinguishable from PNs grown in primary culture in terms of gross morphology, spine length, and spine density. Furthermore, mESC-derived PNs express Calbindin D28K, IP3R1, IRBIT, PLCβ4, PSD93, and myosin IIB-B2, all of which are either PN-specific or highly expressed in PNs. Moreover, we show that mESC-derived PNs form synapses with GN-like cells as in primary culture, express proteins driven by the PN-specific promoter Pcp2/L7, and exhibit the defect in spine ER inheritance seen in PNs isolated from dilute-lethal (myosin Va-null) mice when expressing a Pcp2/L7-driven miRNA directed against myosin Va. Finally, we define a novel extracellular matrix formulation that reproducibly yields monolayer cultures conducive for high-resolution imaging. Our improved method for differentiating mESCs into PNs should facilitate the dissection of molecular mechanisms and disease phenotypes in PNs.
... Only a total of 17 human and mouse genes had FDSIs in which the distinctness arises from distinct expression patterns. For example, the mouse gene Myh10 has two FDSIs, named B1 and B2 by the authors [23]. Cells in the brainstem express B1 to promote normal migration of facial neurons, while cells in the cerebellum expressed B2 to promote normal cerebellar Purkinje cell development. ...
Background:
Although most genes in mammalian genomes have multiple isoforms, an ongoing debate is whether these isoforms are all functional as well as the extent to which they increase the functional repertoire of the genome. To ground this debate in data, it would be helpful to have a corpus of experimentally-verified cases of genes which have functionally distinct splice isoforms (FDSIs).
Results:
We established a curation framework for evaluating experimental evidence of FDSIs, and analyzed over 700 human and mouse genes, strongly biased towards genes that are prominent in the alternative splicing literature. Despite this bias, we found experimental evidence meeting the classical definition for functionally distinct isoforms for ~ 5% of the curated genes. If we relax our criteria for inclusion to include weaker forms of evidence, the fraction of genes with evidence of FDSIs remains low (~ 13%). We provide evidence that this picture will not change substantially with further curation and conclude there is a large gap between the presumed impact of splicing on gene function and the experimental evidence. Furthermore, many functionally distinct isoforms were not traceable to a specific isoform in Ensembl, a database that forms the basis for much computational research.
Conclusions:
We conclude that the claim that alternative splicing vastly increases the functional repertoire of the genome is an extrapolation from a limited number of empirically supported cases. We also conclude that more work is needed to integrate experimental evidence and genome annotation databases. Our work should help shape research around the role of splicing on gene function from presuming large general effects to acknowledging the need for stronger experimental evidence.
... MYH10 and MYH14 are located on chromosome 17 and 19, respectively. Both of these motor proteins express two tissue-specific splice variants (Kim et al. 2005(Kim et al. , 2008Ma et al. 2006). Interestingly, myosin IIA, myosin IIB, and myosin IIC are expressed exclusively in non-muscle cells, hence non-muscle myosin II motor proteins (Golomb et al. 2004;Leal et al. 2003;Simons et al. 1991;Toothaker et al. 1991). ...
Man-made machines mediate a diverse range of human activities in modern world, so are natural myosin motor proteins in driving multiple aspects of cellular life. Myosins belong to a special group of proteins called mechanochemical enzymes or colloquially molecular machines/motor proteins because of their ability to move on intracellular tracks and convert cellular free energy released from ATP into mechanical work. Every cell in the human body is equipped with polymerization, cytoskeletal, rotary, nucleic acid, myosin III, and prestin type motor proteins. These molecular machines with cell-specific expression perform dedicated functions perhaps as a part of nature’s strategy for cell origin and diversification. The mechanical work performed by these cellular motor proteins intersects with every facet of cell biology. Indeed, these motor proteins drive several cellular activities that are essential for mediating reproduction, childbirth, growth, development, immunity, and singing a courtship song in fruit flies as well as predisposing human beings to a certain degree of risk for various pathological conditions and diseases. No biological cell can function and operate without the involvement of these multifunctional molecular machines. The present chapter is about the discovery, current understanding, and recent advances in various aspects of myosin motor proteins as well as their regulation and relevance to human health and diseases.
... The failure to detect the third transcript may have been caused by the samples used. Different AS events occur in different tissues and at different developmental stages (Itoh and Adelstein 1995;Ma et al., 2006). We used fetus cattle samples, but previous studies included 12-month-old male dairy goats. ...
... Brain development occurs earlier than that in the testis during the prenatal period, but conservative AS transcripts show higher expression levels than nonconservative AS transcripts. These results suggest that TMEM95 may have other vital functions in the brain, such as the regulation of brain development (Ma et al., 2006). ...
