Machon O, etal., BMC Dev Biol. 2015 Nov 6;15:40. doi: 10.1186/s12861-015-0093-6.
BACKGROUND: TALE-class homeodomain transcription factors Meis and Pbx play important roles in formation of the embryonic brain, eye, heart, cartilage or hematopoiesis. Loss-of-function studies of Pbx1, 2 and 3 and Meis1 documented specific functions in embryogenesis, however, functional studies of <
span style='font-weight:700;'>Meis2 in mouse are still missing. We have generated a conditional allele of Meis2 in mice and shown that systemic inactivation of the Meis2 gene results in lethality by the embryonic day 14 that is accompanied with hemorrhaging. RESULTS: We show that neural crest cells express Meis2 and Meis2-defficient embryos display defects in tissues that are derived from the neural crest, such as an abnormal heart outflow tract with the persistent truncus arteriosus and abnormal cranial nerves. The importance of Meis2 for neural crest cells is further confirmed by means of conditional inactivation of Meis2 using crest-specific AP2alpha-IRES-Cre mouse. Conditional mutants display perturbed development of the craniofacial skeleton with severe anomalies in cranial bones and cartilages, heart and cranial nerve abnormalities. CONCLUSIONS: Meis2-null mice are embryonic lethal. Our results reveal a critical role of Meis2 during cranial and cardiac neural crest cells development in mouse.
Louw JJ, etal., Am J Med Genet A. 2015 May;167A(5):1142-6. doi: 10.1002/ajmg.a.36989. Epub 2015 Feb 25.
MEIS2 has been associated with cleft palate and cardiac septal defects as well as varying degrees of intellectual disability. We present a female patient with a more severe phenotype compared to previous reported patients. She has multiple congenital malformatio
ns; cleft palate and congenital heart defect characterized by septal defects and aortic coarctation. She has severe feeding problems, facial dysmorphism, severely delayed gross motor and verbal development, and autism spectrum disorder. Facial dysmorphism consisting of bitemporal narrowing, arched and laterally extended eyebrows, mild upslanting palpebral fissures, deep-set eyes, a tented upper lip, thin upper vermilion, full lower vermilion, broad first ray of hands and feet, a gap between the first and second toes, and syndactyly of toe II-III. Exome sequencing revealed a non-frameshift deletion (c.998_1000del:p.Arg333del) of three base pairs in the MEIS2 homeodomain. The more severe phenotype is most probably due to dominant-negative mechanisms. This is the first report showing a de novo small intragenic mutation in MEIS2 and further confirms the important role of this gene in normal development.
Johansson S, etal., Am J Med Genet A. 2014 Jul;164A(7):1622-6. doi: 10.1002/ajmg.a.36498. Epub 2014 Mar 26.
MEIS2 is a homeodomain-containing transcription factor of the TALE superfamily that has been proven important for development. We confirm and extend a recent single clinical report stating that deletions in MEIS2 can cause c
left palate [Crowley et al. (2010); Am J Med Genet 152A:1326-1327]. Here we report on five additional patients with 15q14 deletions of sizes 0.6, 0.6, 1.0, 1.9, and 4.8 Mb, respectively, all involving MEIS2. In addition, we present a family with four affected individuals and an intragenic 58 kb direct duplication disrupting MEIS2. In total, 7/9 cases had clefting, from mild (submucous cleft palate) to severe (cleft lip and palate), and 3/9 cases had ventricular septal defects. All cases had delayed motor development and most had learning disability, at worst in the mild intellectual disability range. The cases had overlapping facial features (broad forehead, finely arched eyebrows, mildly shortened philtrum, and tented upper lip) but individually they were not considered to be dysmorphic. Our results show that MEIS2 is a gene needed for palate closure. In syndromic cases of cleft palate, MEIS2 should be considered among the candidate genes, for example, in cases without 22q11.2 deletions.
Wu YH, etal., Int J Mol Sci. 2015 Oct 23;16(10):25199-213. doi: 10.3390/ijms161025199.
Cardiomyocyte progenitor cells play essential roles in early heart development, which requires highly controlled cellular organization. microRNAs (miRs) are involved in various cell behaviors by post-transcriptional regulation of target genes. However, the roles of miRNAs in human cardiomyocyte prog
enitor cells (hCMPCs) remain to be elucidated. Our previous study showed that miR-134 was significantly downregulated in heart tissue suffering from congenital heart disease, underlying the potential role of miR-134 in cardiogenesis. In the present work, we showed that the upregulation of miR-134 reduced the proliferation of hCMPCs, as determined by EdU assay and Ki-67 immunostaining, while the inhibition of miR-134 exhibited an opposite effect. Both up- and downregulation of miR-134 expression altered the transcriptional level of cell-cycle genes. We identified Meis2 as the target of miR-134 in the regulation of hCMPC proliferation through bioinformatic prediction, luciferase reporter assay and western blot. The over-expression of Meis2 mitigated the effect of miR-134 on hCMPC proliferation. Moreover, miR-134 did not change the degree of hCMPC differentiation into cardiomyocytes in our model, suggesting that miR-134 is not required in this process. These findings reveal an essential role for miR-134 in cardiomyocyte progenitor cell biology and provide new insights into the physiology and pathology of cardiogenesis.
Jeong JH, etal., Mol Cell. 2017 Jan 5;65(1):154-167. doi: 10.1016/j.molcel.2016.11.034. Epub 2016 Dec 29.
Androgen deprivation therapy is the most effective treatment for advanced prostate cancer, but almost all cancer eventually becomes castration resistant, and the underlying mechanisms are largely unknown. Here, we show that an intrinsic constitutively activated feedforward signaling circuit composed
of IκBα/NF-κB(p65), miR-196b-3p, Meis2, and PPP3CC is formed during the emergence of castration-resistant prostate cancer (CRPC). This circuit controls the expression of stem cell transcription factors that drives the high tumorigenicity of CRPC cells. Interrupting the circuit by targeting its individual components significantly impairs the tumorigenicity and CRPC development. Notably, constitutive activation of IκBα/NF-κB(p65) in this circuit is not dependent on the activation of traditional IKKß/NF-κB pathways that are important in normal immune responses. Therefore, our studies present deep insight into the bona fide mechanisms underlying castration resistance and provide the foundation for the development of CRPC therapeutic strategies that would be highly efficient while avoiding indiscriminate IKK/NF-κB inhibition in normal cells.
Deletions on chromosome 15q14 are a known chromosomal cause of cleft palate, typically co-occurring with intellectual disability, facial dysmorphism, and congenital heart defects. The identification of patients with loss-of-function variants in MEIS2, a gene wit
hin this deletion, suggests that these features are attributed to haploinsufficiency of MEIS2. To further delineate the phenotypic spectrum of the MEIS2-related syndrome, we collected 23 previously unreported patients with either a de novo sequence variant in MEIS2 (9 patients), or a 15q14 microdeletion affecting MEIS2 (14 patients). All but one de novo MEIS2 variant were identified by whole-exome sequencing. One variant was found by targeted sequencing of MEIS2 in a girl with a clinical suspicion of this syndrome. In addition to the triad of palatal defects, heart defects, and developmental delay, heterozygous loss of MEIS2 results in recurrent facial features, including thin and arched eyebrows, short alae nasi, and thin vermillion. Genotype-phenotype comparison between patients with 15q14 deletions and patients with sequence variants or intragenic deletions within MEIS2, showed a higher prevalence of moderate-to-severe intellectual disability in the former group, advocating for an independent locus for psychomotor development neighboring MEIS2.
Sun C, etal., Biochem Biophys Res Commun. 2019 Feb 5;509(2):455-461. doi: 10.1016/j.bbrc.2018.12.040. Epub 2018 Dec 26.
AIM: Calcific aortic valve disease (CAVD) is the most common valvular disease worldwide. The osteoblastic transdifferentiation of aortic valve interstitial cells (VICs) is the essential process of CAVD, but the underlying mechanisms are poorly understood. Aortic VICs are generated from ep
ithelial-to-mesenchymal transition (EMT) and migration of neural crest cells (NCCs).Meis2 has been associated with EMT and NCCs migration during development, but its role in CAVD is unknown. This study aims to elucidate the specific functions of Meis2 and its downstream targets in aortic valve calcification. MATERIAL AND METHODS: Levels of Meis2 were examined in calcified (n = 30) and normal (n = 30) human aortic valve tissues, respectively. Meis2 was inhibited in porcine aortic VICs in vitro, and the effect on osteoblastic transdifferentiation and its downstream pathway were studied. RESULTS: Meis2 gene and protein expression decreased significantly in calcified human aortic valve tissue compared with the normal ones. Inhibiting Meis2 by siRNAs reduced the gene and protein expression of Notch1 and Twist1, and induced the osteoblastic transdifferentiation of the porcine aortic VICs in vitro. CONCLUSIONS: The present study indicated that Meis2 repress the osteoblastic transdifferentiation of aortic VICs through the Notch1/Twist1 signaling pathway. The Results identify Meis2 as a potential intervention target for the prevention of CAVD.
BACKGROUND: The bat has strikingly divergent forelimbs (long digits supporting wing membranes) and hindlimbs (short, typically free digits) due to the distinct requirements of both aerial and terrestrial locomotion. During embryonic development, the morphology of the bat forelimb deviates dramatica
lly from the mouse and chick, offering an alternative paradigm for identifying genes that play an important role in limb patterning. RESULTS: Using transcriptome analysis of developing Natal long-fingered bat (Miniopterus natalensis) fore- and hindlimbs, we demonstrate that the transcription factor Meis2 has a significantly higher expression in bat forelimb autopods compared to hindlimbs. Validation by reverse transcriptase and quantitative polymerase chain reaction (RT-qPCR) and whole mount in situ hybridisation shows that Meis2, conventionally known as a marker of the early proximal limb bud, is upregulated in the bat forelimb autopod from CS16. Meis2 expression is localised to the expanding interdigital webbing and the membranes linking the wing to the hindlimb and tail. In mice, Meis2 is also expressed in the interdigital region prior to tissue regression. This interdigital Meis2 expression is not activated by retinoic acid (RA) signalling as it is present in the retained interdigital tissue of Rdh10 (trex/trex) mice, which lack RA. Additionally, genes encoding RA-synthesising enzymes, Rdh10 and Aldh1a2, and the RA nuclear receptor Rarbeta are robustly expressed in bat fore- and hindlimb interdigital tissues indicating that the mechanism that retains interdigital tissue in bats also occurs independently of RA signalling. CONCLUSIONS: Mammalian interdigital Meis2 expression, and upregulation in the interdigital webbing of bat wings, suggests an important role for Meis2 in autopod development. Interdigital Meis2 expression is RA-independent, and retention of interdigital webbing in bat wings is not due to the suppression of RA-induced cell death. Rather, RA signalling may play a role in the thinning (rather than complete loss) of the interdigital tissue in the bat forelimb, while Meis2 may interact with other factors during both bat and mouse autopod development to maintain a pool of interdigital cells that contribute to digit patterning and growth.
Yakushiji-Kaminatsui N, etal., Development. 2016 Jan 15;143(2):276-85. doi: 10.1242/dev.127506. Epub 2015 Dec 16.
Polycomb group (PcG) proteins play a pivotal role in silencing developmental genes and help to maintain various stem and precursor cells and regulate their differentiation. PcG factors also regulate dynamic and complex regional specification, particularly in mammals, but this activity is mechanistic
ally not well understood. In this study, we focused on proximal-distal (PD) patterning of the mouse forelimb bud to elucidate how PcG factors contribute to a regional specification process that depends on developmental signals. Depletion of the RING1 proteins RING1A (RING1) and RING1B (RNF2), which are essential components of Polycomb repressive complex 1 (PRC1), led to severe defects in forelimb formation along the PD axis. We show that preferential defects in early distal specification in Ring1A/B-deficient forelimb buds accompany failures in the repression of proximal signal circuitry bound by RING1B, including Meis1/2, and the activation of distal signal circuitry in the prospective distal region. Additional deletion of Meis2 induced partial restoration of the distal gene expression and limb formation seen in the Ring1A/B-deficient mice, suggesting a crucial role for RING1-dependent repression of Meis2 and likely also Meis1 for distal specification. We suggest that the RING1-MEIS1/2 axis is regulated by early PD signals and contributes to the initiation or maintenance of the distal signal circuitry.
