Embryonic expression of <i>EphA</i> receptor genes in mice supports their candidacy for involvement in cleft lip and palate

Agrawal, Puja; Wang, Michael; Kim, Seungil; Lewis, Ace E.; Bush, Jeffrey O.

doi:10.1002/dvdy.24170

Cited by 12 publications

(11 citation statements)

References 36 publications

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“…Interestingly, though complete loss of EPHB1, EPHB2, and EPHB3 resulted in a dramatic reduction in cell segregation in Efnb1 +/Δ ; Ephb1 -/-; Ephb2 -/-; Ephb3 -/embryos, segregation was not completely abolished, suggesting that additional receptors may play a role. Several EPHA receptors are strongly expressed in the secondary palate mesenchyme, including EPHA4, which was reported to interact with EPHRIN-B1 when overexpressed in Cos7 cells [69,70].…”

Section: Discussionmentioning

confidence: 99%

Aberrant cell segregation in the craniofacial primordium and the emergence of facial dysmorphology in craniofrontonasal syndrome

et al. 2020

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Craniofrontonasal syndrome (CFNS) is a rare X-linked disorder characterized by craniofacial, skeletal, and neurological anomalies and is caused by mutations in EFNB1. Heterozygous females are more severely affected by CFNS than hemizygous males, a phenomenon called cellular interference that results from EPHRIN-B1 mosaicism. In Efnb1 heterozygous mice, mosaicism for EPHRIN-B1 results in cell sorting and more severe phenotypes than Efnb1 hemizygous males, but how craniofacial dysmorphology arises from cell segregation is unknown and CFNS etiology therefore remains poorly understood. Here, we couple geometric morphometric techniques with temporal and spatial interrogation of embryonic cell segregation in mouse mutant models to elucidate mechanisms underlying CFNS pathogenesis. By generating EPHRIN-B1 mosaicism at different developmental timepoints and in specific cell populations, we find that EPHRIN-B1 regulates cell segregation independently in early neural development and later in craniofacial development, correlating with the emergence of quantitative differences in face shape. Whereas specific craniofacial shape changes are qualitatively similar in Efnb1 heterozygous and hemizygous mutant embryos, heterozygous embryos are quantitatively more severely affected, indicating that Efnb1 mosaicism exacerbates loss of function phenotypes rather than having a neomorphic effect. Notably, neural tissue-specific disruption of Efnb1 does not appear to contribute to CFNS craniofacial dysmorphology, but its disruption within neural crest cell-derived mesenchyme results in phenotypes very similar to widespread loss. EPHRIN-B1 can bind and signal with EPHB1, EPHB2, and EPHB3 receptor tyrosine kinases, but the signaling partner(s) relevant to CFNS are unknown. Geometric morphometric analysis of an allelic series of Ephb1; Ephb2; Ephb3 mutant embryos indicates that EPHB2 and EPHB3 are key receptors mediating Efnb1 hemizygous-like phenotypes, but the complete loss of EPHB1-3 does not fully

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Section: Discussionmentioning

confidence: 99%

Aberrant cell segregation in the craniofacial primordium and the emergence of facial dysmorphology in craniofrontonasal syndrome

et al. 2020

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“…EPHA3 is expressed in the palatal shelves, face and middle ear of E14.5 mouse embryos (Visel et al, 2004 ). More recently, it has been suggested that mutations in EPHA family genes may cause cleft lip and palate (Agrawal et al, 2014 ). Mutations in the KIF7 gene have been reported to cause Acrocallosal syndrome, which presents with a wide range of craniofacial abnormalities including macrocephaly, hypertelorism, short nose, broad nasal bridge, short philtrum with upturned upper lip, high and narrow palate (Walsh et al, 2013 ).…”

Section: Discussionmentioning

confidence: 99%

Quantitative trait loci affecting the 3D skull shape and size in mouse and prioritization of candidate genes in-silico

et al. 2015

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Citation:Maga AM, Navarro N, Cunningham ML and Cox TC (2015) Quantitative trait loci affecting the 3D skull shape and size in mouse and prioritization of candidate genes in-silico. Front. Physiol. 6:92. doi: 10.3389/fphys.2015.00092 Quantitative trait loci affecting the 3D skull shape and size in mouse and prioritization of candidate genes in-silico We describe the first application of high-resolution 3D micro-computed tomography, together with 3D landmarks and geometric morphometrics, to map QTL responsible for variation in skull shape and size using a backcross between C57BL/6J and A/J inbred strains. Using 433 animals, 53 3D landmarks, and 882 SNPs from autosomes, we identified seven QTL responsible for the skull size (SCS.qtl) and 30 QTL responsible for the skull shape (SSH.qtl). Size, sex, and direction-of-cross were all significant factors and included in the analysis as covariates. All autosomes harbored at least one SSH.qtl, sometimes up to three. Effect sizes of SSH.qtl appeared to be small, rarely exceeding 1% of the overall shape variation. However, they account for significant amount of variation in some specific directions of the shape space. Many QTL have stronger effect on the neurocranium than expected from a random vector that will parcellate uniformly across the four cranial regions. On the contrary, most of QTL have an effect on the palate weaker than expected. Combined interval length of 30 SSH.qtl was about 315 MB and contained 2476 known protein coding genes. We used a bioinformatics approach to filter these candidate genes and identified 16 high-priority candidates that are likely to play a role in the craniofacial development and disorders. Thus, coupling the QTL mapping approach in model organisms with candidate gene enrichment approaches appears to be a feasible way to identify high-priority candidates genes related to the structure or tissue of interest.

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“…Of the selected EphA receptors, we found that only EphA7 was co-expressed with EphA3 in the lung mesenchyme. Interestingly, a recent study has suggested that there is functional compensation of EphA3 loss by EphA7 co-expression during palate development, as compound homozygous mutation of EphA3 and EphA4 failed to cause defective midfacial development ( Agrawal et al, 2014 ). Furthermore, a truncated form of EPHA7 has been reported to act as a tumor suppressor in follicular lymphoma ( Oricchio et al, 2011 ), and it would thus be interesting to study its potential role in lung tumor suppression in conjunction with EphA3 loss of function.…”

Section: Discussionmentioning

confidence: 99%

The putative tumor suppressor geneEphA3fails to demonstrate a crucial role in murine lung tumorigenesis or morphogenesis

Lahtela

Pradhan

Närhi

et al. 2015

Disease Models &Amp; Mechanisms

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Treatment of non-small cell lung cancer (NSCLC) is based on histological analysis and molecular profiling of targetable driver oncogenes. Therapeutic responses are further defined by the landscape of passenger mutations, or loss of tumor suppressor genes. We report here a thorough study to address the physiological role of the putative lung cancer tumor suppressor EPH receptor A3 (EPHA3), a gene that is frequently mutated in human lung adenocarcinomas. Our data shows that homozygous or heterozygous loss of EphA3 does not alter the progression of murine adenocarcinomas that result from Kras mutation or loss of Trp53, and we detected negligible postnatal expression of EphA3 in adult wild-type lungs. Yet, EphA3 was expressed in the distal mesenchyme of developing mouse lungs, neighboring the epithelial expression of its Efna1 ligand; this is consistent with the known roles of EPH receptors in embryonic development. However, the partial loss of EphA3 leads only to subtle changes in epithelial Nkx2-1, endothelial Cd31 and mesenchymal Fgf10 RNA expression levels, and no macroscopic phenotypic effects on lung epithelial branching, mesenchymal cell proliferation, or abundance and localization of CD31-positive endothelia. The lack of a discernible lung phenotype in EphA3-null mice might indicate lack of an overt role for EPHA3 in the murine lung, or imply functional redundancy between EPHA receptors. Our study shows how biological complexity can challenge in vivo functional validation of mutations identified in sequencing efforts, and provides an incentive for the design of knock-in or conditional models to assign the role of EPHA3 mutation during lung tumorigenesis.

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Embryonic expression of EphA receptor genes in mice supports their candidacy for involvement in cleft lip and palate

Cited by 12 publications

References 36 publications

Aberrant cell segregation in the craniofacial primordium and the emergence of facial dysmorphology in craniofrontonasal syndrome

Aberrant cell segregation in the craniofacial primordium and the emergence of facial dysmorphology in craniofrontonasal syndrome

Quantitative trait loci affecting the 3D skull shape and size in mouse and prioritization of candidate genes in-silico

The putative tumor suppressor geneEphA3fails to demonstrate a crucial role in murine lung tumorigenesis or morphogenesis

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