Conditional deletion of the human ortholog gene Dicer1 in Pax2-Cre expression domain impairs orofacial development

Barritt, Laura C.; Miller, Joseph M.; Scheetz, Laura R.; Gardner, Kelsey; Pierce, Marsha L.; Soukup, Garrett A.; Rocha-Sánchez, Sonia M.

doi:10.4103/0971-6866.107984

Cited by 28 publications

(14 citation statements)

References 36 publications

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“…Indeed, the importance of miRNAs for craniofacial development in general, is supported by the severe craniofacial malformations seen in mouse embryos with a conditional deletion of Dicer in Wnt-1 expressing neural crest cells (Zehir et al ., 2010). Loss of Dicer expression in Pax2 -expressing cells also leads to craniofacial defects, including cleft palate and midfacial hypoplasia (Barritt et al ., 2012). We have thus conducted the current study to identify miRNAs that are expressed in the facial processes that contribute to the formation of the upper lip.…”

Section: Discussionmentioning

confidence: 99%

MicroRNA expression profiling of the developing murine upper lip

et al. 2014

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Clefts of the lip and palate are thought to be caused by genetic and environmental insults but the role of epigenetic mechanisms underlying this common birth defect are unknown. We analyzed the expression of over 600 microRNAs in the murine medial nasal and maxillary processes isolated on GD10.0-GD11.5 to identify those expressed during development of the upper lip and analyzed spatial expression of a subset. A total of 169 microRNAs were differentially expressed across gestation days 10.0 to 11.5 in the medial nasal processes, and 77 in the maxillary processes of the first branchial arch with 49 common to both. Of the microRNAs exhibiting the largest percent increase in both facial processes were 5 members of the Let-7 family. Among those with the greatest decrease in expression from GD10.0 to GD11.5 were members of the microRNA-302/367 family that have been implicated in cellular reprogramming. The distribution of expression of microRNA-199a-3p and Let-7i was determined by in situ hybridization and revealed widespread expression in both medial nasal and maxillary facial processes while that for microRNA-203 was much more limited. MicroRNAs are dynamically expressed in the tissues that form the upper lip and several were identified that target mRNAs known to be important for its development, including those that regulate the two main isoforms of p63 (microRNA-203 and microRNA-302/367 family). Integration of these data with corresponding proteomic data sets will lead to a greater appreciation of epigenetic regulation of lip development and provide a better understanding of potential causes of cleft lip.

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Section: Discussionmentioning

confidence: 99%

MicroRNA expression profiling of the developing murine upper lip

et al. 2014

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“…Conditional deletion of Dicer controlled by Pax2-Cre or Wnt1-Cre leads to perinatal death with severe craniofacial malformations in mice (Sheehy et al, 2010; Zehir et al, 2010; Nie et al, 2011; Barritt et al, 2012). Pax2 and Wnt1 expression is specific for cNC-derived mesenchyme from embryonic day (E) 7.5 and 8.5, respectively.…”

Section: Introductionmentioning

confidence: 99%

“…This may occur through miR-452, which is highly expressed in cNC-derived mesenchyme at E10.5 in the first pharyngeal arch and regulates Fgf8 and Dlx2 expression. In the Pax2-Cre; Dicer f / f mouse, a similarly large increase in apoptosis is present as well as a lower density of proliferating cells (Barritt et al, 2012). A Wnt1 -Cre; Dgcr8 f / f mouse exhibited a phenotype similar to that of the Dicer deletion and showed lower levels of pERK1/2, a kinase involved in another cell survival pathway (Chapnik et al, 2012).…”

Section: Introductionmentioning

confidence: 99%

MicroRNAs in Palatogenesis and Cleft Palate

et al. 2017

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Palatogenesis requires a precise spatiotemporal regulation of gene expression, which is controlled by an intricate network of transcription factors and their corresponding DNA motifs. Even minor perturbations of this network may cause cleft palate, the most common congenital craniofacial defect in humans. MicroRNAs (miRNAs), a class of small regulatory non-coding RNAs, have elicited strong interest as key regulators of embryological development, and as etiological factors in disease. MiRNAs function as post-transcriptional repressors of gene expression and are therefore able to fine-tune gene regulatory networks. Several miRNAs are already identified to be involved in congenital diseases. Recent evidence from research in zebrafish and mice indicates that miRNAs are key factors in both normal palatogenesis and cleft palate formation. Here, we provide an overview of recently identified molecular mechanisms underlying palatogenesis involving specific miRNAs, and discuss how dysregulation of these miRNAs may result in cleft palate.

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“…Of relevance, mutation of this cluster has been reported to cause cleft lip and palate (CL/P) by modulating the expression of Tbx1 , Tbx3 and Fgf10 , factors considered essential for midfacial development [27]. Barritt et al [28] identified complete palatal clefts when Dicer1 was ablated in the Pax2 - Cre / Dicer1 conditional knockout mice. In this model, knockout of Dicer1 did not affect early events in palatogenesis, such as cranial neural crest (CNC) migration to the first pharyngeal arch or the formation of palatal shelves, but fusion and mineralization of the palatal shelves were severely compromised.…”

Section: Introductionmentioning

confidence: 99%

Methylated MicroRNA Genes of the Developing Murine Palate

Seelan¹,

Mukhopadhyay²,

Warner³

et al. 2015

MIRNA

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Environmental factors contribute to the etiology of cleft palate (CP). Environmental factors can also affect gene expression via alterations in DNA methylation suggesting a possible mechanism for the induction of CP. Identification of genes methylated during development of the secondary palate provides the basis for examination of the means by which environmental factors may adversely influence palatal ontogeny. We previously characterized the methylome of the developing murine secondary palate focusing primarily on protein-encoding genes. We now extend this study to include methylated microRNA (miRNA) genes. A total of 42 miRNA genes were found to be stably methylated in developing murine palatal tissue. Twenty eight of these were localized within host genes. Gene methylation was confirmed by pyrosequencing of selected miRNA genes. Integration of methylated miRNA gene and expression datasets identified 62 miRNAs, 69% of which were non-expressed. For a majority of genes (83%), upstream CpG islands (CGIs) were highly methylated suggesting down-regulation of CGI-associated promoters. DAVID and IPA analyses indicated that both expressed and non-expressed miRNAs target identical signaling pathways and biological processes associated with palatogenesis. Furthermore, these analyses also identified novel signaling pathways whose roles in palatogenesis remain to be elucidated. In summary, we identify methylated miRNA genes in the developing murine secondary palate, correlate miRNA gene methylation with expression of their cognate miRNA transcripts, and identify pathways and biological processes potentially mediated by these miRNAs.

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Conditional deletion of the human ortholog gene Dicer1 in Pax2-Cre expression domain impairs orofacial development

Cited by 28 publications

References 36 publications

MicroRNA expression profiling of the developing murine upper lip

MicroRNA expression profiling of the developing murine upper lip

MicroRNAs in Palatogenesis and Cleft Palate

Methylated MicroRNA Genes of the Developing Murine Palate

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