Author response: The splicing regulators Esrp1 and Esrp2 direct an epithelial splicing program essential for mammalian development

Bebee, Thomas W.; Park, Juw Won; Sheridan, Katherine I; Warzecha, Claude C.; Cieply, Benjamin; Rohacek, Alex M; Xing, Yi; Carstens, Russ P.

doi:10.7554/elife.08954.029

Cited by 6 publications

(1 citation statement)

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“…Interestingly, ZEB1 directly represses the ESRP1 locus in breast cancer cells (Preca et al, 2015). Esrp1 −/− mice have bilateral cleft lip and palate and die neonatally, whereas Esrp2 −/− mice have no overt phenotype (Bebee et al, 2015). Esrp1 −/− ;Esrp2 −/− mice also display agenesis of lungs and salivary glands, but survive until E18.5.…”

Section: Discussionmentioning

confidence: 99%

Inactivation of Zeb1 in GRHL2-deficient mouse embryos rescues mid-gestation viability and secondary palate closure

Carpinelli

Vries

Auden

et al. 2020

Disease Models &Amp; Mechanisms

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Cleft lip and palate are common birth defects resulting from failure of the facial processes to fuse during development. The mammalian grainyhead-like (Grhl1-3) genes play key roles in a number of tissue fusion processes including neurulation, epidermal wound healing and eyelid fusion. One family member, Grhl2, is expressed in the epithelial lining of the first pharyngeal arch in mice at embryonic day (E)10.5, prompting analysis of the role of this factor in palatogenesis. Grhl2null mice die at E11.5 with neural tube defects and a cleft face phenotype, precluding analysis of palatal fusion at a later stage of development. However, in the first pharyngeal arch of Grhl2-null embryos, dysregulation of transcription factors that drive epithelialmesenchymal transition (EMT) occurs. The aberrant expression of these genes is associated with a shift in RNA-splicing patterns that favours the generation of mesenchymal isoforms of numerous regulators. Driving the EMT perturbation is loss of expression of the EMT-suppressing transcription factors Ovol1 and Ovol2, which are direct GRHL2 targets. The expression of the miR-200 family of microRNAs, also GRHL2 targets, is similarly reduced, resulting in a 56-fold upregulation of Zeb1 expression, a major driver of mesenchymal cellular identity. The critical role of GRHL2 in mediating cleft palate in Zeb1 −/− mice is evident, with rescue of both palatal and facial fusion seen in Grhl2 −/− ;Zeb1 −/− embryos. These findings highlight the delicate balance between GRHL2/ZEB1 and epithelial/mesenchymal cellular identity that is essential for normal closure of the palate and face. Perturbation of this pathway may underlie cleft palate in some patients.

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Section: Discussionmentioning

confidence: 99%

Inactivation of Zeb1 in GRHL2-deficient mouse embryos rescues mid-gestation viability and secondary palate closure

Carpinelli

Vries

Auden

et al. 2020

Disease Models &Amp; Mechanisms

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Cleft lip and cleft palate (CL/P) inEsrp1KO mice is associated with alterations in Wnt signaling and epithelial-mesenchymal crosstalk

Zhang

et al. 2019

Preprint

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Running Title: Altered Wnt signaling and CL/P in Esrp1 KO mice (32 characters) SUMMARY STATEMENT 3Ablation of the epithelial-specific splicing factor Esrp1 leads to cleft lip and cleft palate (CL/P) and this 4 study identifies alterations in Wnt signaling during face formation that may partly underlie this defect. 5 6 7 ABSTRACT 8 9Cleft lip is one of the most highly prevalent birth defects in human patients. However, there remain a 10 limited number of mouse models of cleft lip and thus much work is needed to further characterize genes 11 and mechanisms that lead to this disorder. It is well established that crosstalk between epithelial and 12 mesenchymal cells underlies formation of the face and palate, yet the basic molecular events mediating 13 this crosstalk are still poorly understood. We previously demonstrated that mice with ablation of the 14 epithelial-specific splicing factor Esrp1 have fully penetrant bilateral CL/P. In this study we further 15 investigated the mechanisms by which ablation of Esrp1 leads to cleft lip as well as cleft palate. These 16 studies included a detailed analysis of the changes in splicing and total gene expression in embryonic 17 ectoderm during formation of the face as well as gene expression changes in adjacent mesenchyme. We 18 identified altered expression in components of pathways previously implicated in cleft lip and/or palate, 19 including numerous components of the Wnt signaling pathway. These findings illustrate that maintenance 20 of an Esrp1 regulated epithelial splicing program is essential for face development through regulation of 21 key signaling pathways. 22 23 24 25 26 27 28 29Cleft lip and/or palate (CL/P) are among the most common congenital birth defects, affecting 30 approximately 1 in 700 live births and affected children face a variety of health and psychosocial 31 problems as well as a need for extensive surgical and dental treatments (Dixon et al., 2011). The causes of 32 CL/P are heterogeneous and include a variety of environmental and genetic factors. Although CL/P can 33 be a component of disease syndromes, most cases of CL/P are non-syndromic. Cleft lip with or without 34 cleft palate (CL/P) is more common in human patients than isolated cleft palate (CP, or CPO) and these 35 disorders are largely genetically and etiologically distinct (Fraser, 1970; Gritli-Linde, 2008).The proper 36 development of the lip and palate is similar between humans and mice and thus mouse models have 37 served an important role in studies to identify genes and characterize pathways that, when disrupted, lead 38 to CL/P or CPO (Gritli-Linde, 2012; Juriloff and Harris, 2008). In mice, formation of the face commences 39 around E9.5 and involves the five facial prominences consisting of mostly neural crest-derived 40 mesenchyme and overlying epithelium; the frontonasal prominence (FNP) and the paired maxillary and 41 mandibular prominences (MXP and MdP) (Jiang et al., 2006). The FNP gives rise to the lateral and 42 medial nasal prominences (LNP and MNP) and these prominence...

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Requirement ofIrf6andEsrp1/2in frontonasal and palatal epithelium to regulate craniofacial and palate morphogenesis in mouse and zebrafish

Carroll

Trevino

et al. 2020

Preprint

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ABSTRACTOrofacial clefts are among the most common human congenital malformations. Irf6 and Esrp1 are two key genes important for palate development, conserved across vertebrates. In the zebrafish, we found that irf6 regulates the expression of esrp1. Using RNAscope, we detailed overlapping Irf6 and Esrp1/2 gene expression in the mouse frontonasal prominence ectoderm, lambda joint periderm, palate and lip epithelium. In the zebrafish, irf6 and esrp1/2 share expression in the pre-gastrulation periderm and the embryonic frontonasal ectoderm, oral epithelium ventral to the anterior neurocranium (ANC), and the developing stomodeum. Genetic disruption of irf6 and esrp1/2 in the zebrafish resulted in cleft of the ANC. In the esrp1/2 zebrafish mutant, cleft of the mouth opening formed and appeared to tether into the ANC cleft. Lineage tracing of the anterior cranial neural crest cells revealed that cleft of the ANC resulted not from migration defect, but from impaired chondrogenesis. Molecular analysis of the aberrant cells localized within the ANC cleft revealed that this cell population espresses sox10, col1a1 and irf6 and is adjacent to cells expressing epithelial krt4. Detailed morphogenetic analysis of mouse Irf6 mutant revealed mesenchymal defects not observed in the Esrp1/2 mutant. Analysis of breeding compound Irf6;Esrp1;Esrp2 mutant suggests that these genes interact where the triple mutant is not observed. Taken together, these studies highlight the complementary analysis of Irf6 and Esrp1/2 in mouse and zebrafish models and captured an unique aberrant embryonic cell population that contributes to cleft pathogenesis. Future work characterizing this unqiue sox10+, col1a1+, irf6+ cell population will yield additional insight into cleft pathogenesis.

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Author response: The splicing regulators Esrp1 and Esrp2 direct an epithelial splicing program essential for mammalian development

Cited by 6 publications

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Inactivation of Zeb1 in GRHL2-deficient mouse embryos rescues mid-gestation viability and secondary palate closure

Inactivation of Zeb1 in GRHL2-deficient mouse embryos rescues mid-gestation viability and secondary palate closure

Cleft lip and cleft palate (CL/P) inEsrp1KO mice is associated with alterations in Wnt signaling and epithelial-mesenchymal crosstalk

Requirement ofIrf6andEsrp1/2in frontonasal and palatal epithelium to regulate craniofacial and palate morphogenesis in mouse and zebrafish

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