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Elmo2 is an essential regulator of carotid artery development

ABSTRACT: Engulfment and cell motility 2 (ELMO2) is a cytoskeletal adaptor protein. Loss of function mutations in ELMO2 are associated with a life-threatening human disease called intraosseous vascular malformation (VMOS). This autosomal recessive disease manifests in the craniofacial area and has no effective treatment, in part due to the poor characterization of its physiopathology. In this study, we report the first detailed characterization of Elmo2 global deletion in mice and showcase the importance of Elmo2 during cardiovascular development. Elmo2 was found to be indispensable for normal morphogenesis of the third pharyngeal arch artery (3rd PAA) which gives rise to the common carotid artery, responsible for the blood supply to the craniofacial region. Global deletion of Elmo2 induces severe dilation in the 3rd PAAs and aneurism formation in the carotid arteries leading to embryonic lethality. Elmo2-deficient embryos showed impaired cytoskeletal organization in neural crest-derived vascular smooth muscle cells (VSMCs) and defects in the endothelial lining of the dilated arteries. Deletion of Elmo2 specifically in neural crest cells phenocopied all the relevant defects observed in the global knockout while gene inactivation in endothelial cells, sympathetic neurons and mature VSMCs had no effect or induced only minor changes in vessel diameter. Furthermore, time-controlled ubiquitous deletion of Elmo2 allowed us to conclude that early gene inactivation is necessary for recapitulating the major defects observed in Elmo2-null embryos. In addition, analysis of cultured neural crest-derived human brain VSMCs showed decreased active RAC1 and F-actin levels upon ELMO2 downregulation, which impair adhesion, spreading and cell contractility. These defects can be rescued in vitro through administration of the F-actin stabilizer Jasplakinolide. Altogether our results highlight a previously unappreciated role for Elmo2 in the physiology of neural crest-derived VSMCs. These findings might be relevant for understanding the cellular mechanisms responsible for VMOS.

ORGANISM(S): Mus musculus

PROVIDER: GSE278960 | GEO | 2025/05/05

REPOSITORIES: GEO

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Project description:Sympathetic neurons of SCG (Superior Cervical Ganglia) send axonal projections either along the external carotid arteries to innervate the salivary glands, or along the internal carotid arteries to the lacrimal and pineal glands, the eye, blood vessels and skin of the head, and the mucosa of the oral and nasal cavities. Previous studies using Wnt1Cre and R26R have defined the neural crest and mesodermal origins of vascular smooth muscle in the heart outflow tract and great vessels, although not specifically of the segments that are relevant for the projections of the SCG neurons. The third pharyngeal arch arteries are lined by neural crest-derived smooth muscle, and consequently, their derivatives, including the entirety of the external carotid arteries and only the base of the internal carotid arteries, also have a neural crest origin. In contrast, the dorsal aortae are lined by smooth muscle that is mesodermal in origin, and as a result, the internal carotid arteries from just above their origination from the common carotid arteries have a mesoderm-derived smooth muscle layer. To address the possibility that guidance cues for SCG neurons are selectively expressed by the external carotid vs. the internal carotid arteries, we isolated these segments of the vasculature from mouse embryos at E13.5 and extracted RNA to screen microarrays for differentially expressed genes. Experiment Overall Design: Vascular segments were isolated from 22 embryos at E13.5, pooled and extracted RNA for microarray screen. Total RNA samples from the internal or the external carotid arteries were subjected for two-round amplification to synthesize cRNA to probe microarray. Neither experimental nor technical replicate was made for this experiment. Experiment Overall Design: Vascular segments were isolated from 22 embryos at E13.5, pooled and extracted RNA for microarray screen. Total RNA samples from the internal or the external carotid arteries were subjected for two-round amplification to synthesize cRNA to probe microarray. Neither experimental nor technical replicate was made for this experiment.

Project description:Orofacial clefts are the most common form of congenital craniofacial malformations worldwide. The etiology of these birth defects is multifactorial, involving genetic and environmental factors. In most cases, however, the underlying causes remain unexplained, precluding molecular understanding of disease mechanisms. Here, we integrated genome-wide association data, targeted re-sequencing of case and control cohorts, cell type-specific epigenomic profiling, and genome architecture analyses, to functionally and molecularly dissect a genomic locus associated with an increased risk of non-syndromic orofacial cleft. We found that common and rare risk variants associated with orofacial cleft intersect with a conserved enhancer (e2p24.2) that becomes activated in cranial neural crest cells—the embryonic cell type responsible for sculpting the craniofacial complex. We mapped e2p24.2 long-range interactions to a topologically associated domain harboring MYCN and DDX1 and demonstrated that both MYCN and DDX1 are required for craniofacial development in chicken embryos. We found that e2p24.2 regulates the expression of MYCN, but not DDX1, in cranial neural crest cells. In turn, DDX1 is a target of the MYC family of transcription factors and a component of the tRNA splicing complex. The loss of DDX1 in cranial neural crest cells resulted in the accumulation of unspliced tRNA fragments, depletion of the mature pool of intron-containing tRNAs, and ribosome stalling at codons decoded by these tRNAs. These effects were accompanied by defects in both global protein synthesis and cranial neural crest cell migration. We further showed that the induction of tRNA fragments is sufficient to disrupt craniofacial development. Together, these results uncovered a molecular mechanism in which impaired tRNA splicing affects neural crest and craniofacial development and positioned MYCN, DDX1, and tRNA processing defects as risk factors in the pathogenesis of orofacial clefts.

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Elmo2 is an essential regulator of carotid artery development

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