Neural tube defects by <i>NUAK1</i> and <i>NUAK2</i> double mutation

Ohmura, Tomomi; Shioi, Go; Hirano, Mariko; Aizawa, Shinichi

doi:10.1002/dvdy.23816

Cited by 34 publications

(33 citation statements)

References 92 publications

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“…Furthermore, the bending profile of the cephalic ectoderm matches to NUAK2 mRNA detection in epithelial structures. These observations are clues pointing to a role for NUAK2 in morphogenesis according to Ohmura et al, (2012). Interestingly, regulation of NUAK2 expression by a dorsally-derived morphogene (BMPs or Wnts) might also give this type of staining.…”

Section: Nuak1 and Nuak2 Expression During Chick Development 383mentioning

confidence: 87%

“…An 810 bp PCR ec,ectoderm;dh,dorsal hinge point;Hn,Hensen's node;lh,lateral hinge point;mh,median hinge point. Scale bar,500 mm. This hypothesis is supported by the phenotype of double knockdown mice (Ohmura et al, 2012). Ohmura et al, concluded that NUAK1 and NUAK2 have complementary functions in the apical constriction and apico-basal elongation associated with dorsal hinge point formation in the cephalic neural plate during the 5-to 10-somite stages.…”

Section: Isolation and Cloning Of Nuak1 And Nuak2 Probesmentioning

confidence: 92%

“…In addition, in these mice, phosphorylated MLC2, F-actin and cortactin fail to effectively concentrate at apical cell surfaces, indicating that NUAK kinases may contribute to apical constriction and cell shape control. NUAK1 and NUAK2 functions have been studied in human (Lu et al, 2013, mouse (Ohmura et al, 2012), D. melanogaster (Amin et al, 2009) and C. elegans (Hoppe et al, 2010). In this article, we report on NUAK1 and NUAK2 mRNA expression in early chick embryos.…”

mentioning

confidence: 95%

“…Although these genes are mainly expressed in the neuroectoderm in mouse, it has been reported that NUAK1 mutants exhibit no apparent gross brain defects, but do have ventral body wall defects (Hirano et al, 2006). Mice deficient in both NUAK1 and NUAK2 display exencephaly, facial clefting, and spina bifida, suggesting partially redundant activity for these two genes (Ohmura et al, 2012). In addition, in these mice, phosphorylated MLC2, F-actin and cortactin fail to effectively concentrate at apical cell surfaces, indicating that NUAK kinases may contribute to apical constriction and cell shape control.…”

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confidence: 99%

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Analysis of NUAK1 and NUAK2 expression during early chick development reveals specific patterns in the developing head

Bekri¹,

Billaud²,

Thélu³

2014

Int. J. Dev. Biol.

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Several human diseases are associated with the NUAK1 and NUAK2 genes. These genes encode kinases, members of the AMPK-related kinases (ARK) gene family. Both NUAK1 and NUAK2 are known targets of the serine threonine kinase LKB1, a tumor suppressor involved in regulating cell polarity. While much is known about their functions in disease, their expression pattern in normal development has not been extensively studied. Here, we present the expression patterns for NUAK1 and NUAK2 in the chick during early-stage embryogenesis, until day 3 (Hamburger and Hamilton stage HH20). Several embryonic structures, in particular the nascent head, showed distinct expression levels. NUAK1 expression was first detected at stage HH6 in the rostral neural folds. It was then expressed (HH7-11) throughout the encephalalon, predominantly in the telencephalon and mesencephalon. NUAK1 expression was also detected in the splanchnic endoderm area at HH8-10, and in the vitellin vein derived from this area, but not in the heart. NUAK2 expression was first detected at stage HH6 in the neural folds. It was then found throughout the encephalon at stage HH20. Particular attention was paid in this study to the dorsal ectoderm at stages HH7 and HH8, where a local deficit or accumulation of NUAK2 mRNA were found to correlate with the direction of curvature of the neural plate. This is the first description of NUAK1 and NUAK2 expression patterns in the chick during early development; it reveals non-identical expression profiles for both genes in neural development. KEY WORDS: NUAK, chick embryo, in situ hybridizationNUAK1 and NUAK2 are members of the novel (Nua) kinases family. Their alternative names include: ARK5 or OMPHK1 for NUAK1; and SNARK or OMPHK2 for NUAK2. They are two of the fourteen known substrates of the serine threonine kinase LKB1 and are part of the AMPK-related protein kinase family (ARK) (Al-Hakim et al., 2005, Hardie and Alessi, 2013, Manning et al., 2002, Suzuki et al., 2003. AMPK is a mammalian homolog of sucrose non-fermentable protein kinase (SNF-1); it is a member of a serine/threonine protein kinase family. Unlike AMPK, which is activated under various stress conditions resulting in decreased ATP concentrations (Scott et al., 2007), ARKs do not have AMP: ATP ratio-sensitive regulatory subunits. Thus, they do not directly participate in adaptive responses to energy balance (Al-Hakim et al., 2005).NUAK1 was first described as supporting AKT-dependent cell survival during nutrient starvation (Suzuki et al., 2003), and has been shown to induce p53 phosphorylation (Hou et al., 2011). NUAK1 expression is now known to be closely associated with metastases, colorectal cancer and is an indicator of poor prognoInt. J. Dev. Biol. 58: 379-384 (2014) sis for glioma (Lu et al., 2013). Recently, it was shown to favor an invasive phenotype in human breast cancer which also depended on AKT signaling. This may be linked to its role in cell adhesion through phosphorylation of the regulatory sub-unit of the myosin light chain 2 (MLC...

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Section: Nuak1 and Nuak2 Expression During Chick Development 383mentioning

confidence: 87%

Section: Isolation and Cloning Of Nuak1 And Nuak2 Probesmentioning

confidence: 92%

mentioning

confidence: 95%

mentioning

confidence: 99%

See 2 more Smart Citations

Analysis of NUAK1 and NUAK2 expression during early chick development reveals specific patterns in the developing head

Bekri¹,

Billaud²,

Thélu³

2014

Int. J. Dev. Biol.

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“…Muscle-specific knock-down of ARK5/NUAK1 causes altered phosphorylation of contractile apparatus proteins, whereas disruption of SNARK/NUAK2 causes an age-dependent reduction in muscle mass (Inazuka et al 2012;Lessard et al 2016). Double knockouts of these orthologs have not been studied in mammalian muscle; these mutants arrest with defects in embryonic morphogenesis (Ohmura et al 2012). Interestingly, in human kidney cells, ARK5 has been shown to regulate nonmuscle myosin light chain phosphorylation (Zagórska et al 2010).…”

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confidence: 99%

The Role of the UNC-82 Protein Kinase in Organizing Myosin Filaments in Striated Muscle ofCaenorhabditis elegans

Schiller¹,

Duchesneau²,

Lane³

et al. 2017

Genetics

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We study the mechanisms that guide the formation and maintenance of the highly ordered actin-myosin cytoskeleton in striated muscle. The UNC-82 kinase of Caenorhabditis elegans is orthologous to mammalian kinases ARK5/NUAK1 and SNARK/ NUAK2. UNC-82 localizes to the M-line, and is required for proper organization of thick filaments, but its substrate and mechanism of action are unknown. Antibody staining of three mutants with missense mutations in the UNC-82 catalytic domain revealed muscle structure that is less disorganized than in the null unc-82(0), but contained distinctive ectopic accumulations not found in unc-82(0). These accumulations contain paramyosin and myosin B, but lack myosin A and myosin A-associated proteins, as well as proteins of the integrin-associated complex. Fluorescently tagged missense mutant protein UNC-82 E424K localized normally in wild type; however, in unc-82(0), the tagged protein was found in the ectopic accumulations, which we also show to label with recently synthesized paramyosin. Recruitment of wild-type UNC-82::GFP to aggregates of differing protein composition in five muscle-affecting mutants revealed that colocalization of UNC-82 and paramyosin does not require UNC-96, UNC-98/ZnF, UNC-89/obscurin, CSN-5, myosin A, or myosin B individually. Dosage effects in paramyosin mutants suggest that UNC-82 acts as part of a complex, in which its stoichiometric relationship with paramyosin is critical. UNC-82 dosage affects muscle organization in the absence of paramyosin, perhaps through myosin B. We present evidence that the interaction of UNC-98/ZnF with myosin A is independent of UNC-82, and that UNC-82 acts upstream of UNC-98/ZnF in a pathway that organizes paramyosin during thick filament assembly.

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UNC‐82/NUAK kinase is required by myosin A, but not myosin B, to assemble and function in the thick filament arms of C. elegans striated muscle

Schiller,

Almuhanna,

Hoppe

2023

Cytoskeleton

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The mechanisms that ensure proper assembly, activity, and turnover of myosin II filaments are fundamental to a diverse range of cellular processes. In Caenorhabditis elegans striated muscle, thick filaments contain two myosins that are functionally distinct and spatially segregated. Using transgenic double mutants, we demonstrate that the ability of increased myosin A expression to restore muscle structure and movement in myosin B mutants requires UNC‐82/NUAK kinase activity. Myosin B function appears unaffected in the kinase‐impaired unc‐82(e1220) mutant: the recessive antimorphic effects on early assembly of paramyosin and myosin A in this mutant are counteracted by increased myosin B expression and exacerbated by loss of myosin B. Using chimeric myosins and motility assays, we mapped the region of myosin A that requires UNC‐82 activity to a 531‐amino‐acid region of the coiled‐coil rod. This region includes the 264‐amino‐acid Region 1, which is sufficient in chimeric myosins to rescue the essential filament‐initiation function of myosin A, as well as two sites that interact with myosin head domains in the Interacting Heads Motif. A specific physical interaction between myosin A and UNC‐82::GFP is supported by GFP labeling of ectopic myosin A filaments but not thin filaments. We hypothesize that UNC‐82 regulates assembly competence of myosin A during parallel assembly in the filament arms.

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Neural tube defects by NUAK1 and NUAK2 double mutation

Cited by 34 publications

References 92 publications

Analysis of NUAK1 and NUAK2 expression during early chick development reveals specific patterns in the developing head

Analysis of NUAK1 and NUAK2 expression during early chick development reveals specific patterns in the developing head

The Role of the UNC-82 Protein Kinase in Organizing Myosin Filaments in Striated Muscle ofCaenorhabditis elegans

UNC‐82/NUAK kinase is required by myosin A, but not myosin B, to assemble and function in the thick filament arms of C. elegans striated muscle

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