2022
DOI: 10.3389/fcell.2022.777887
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Alx1 Deficient Mice Recapitulate Craniofacial Phenotype and Reveal Developmental Basis of ALX1-Related Frontonasal Dysplasia

Abstract: Loss of ALX1 function causes the frontonasal dysplasia syndrome FND3, characterized by severe facial clefting and microphthalmia. Whereas the laboratory mouse has been the preeminent animal model for studying developmental mechanisms of human craniofacial birth defects, the roles of ALX1 in mouse frontonasal development have not been well characterized because the only previously reported Alx1 mutant mouse line exhibited acrania due to a genetic background-dependent failure of cranial neural tube closure. Usin… Show more

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Cited by 16 publications
(23 citation statements)
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“…However, no single clear candidate emerged that was expressed in all Coordinator-positive cell types and could explain the quantitative variation in Coordinator activity. Instead, every cell type expresses multiple HD TFs robustly, with groups of HDs showing overlapping expression in distinct regions of the developing face and limbs, consistent with their previously described association with specific positional identities [41][42][43] (such as along the anterior-posterior axis). For example and as expected, the ALX factors are enriched in the frontonasal prominence, which gives rise to the upper part of the face, whereas DLX factors are enriched in the mandibular prominence, which gives rise to the lower jaw, while the posterior HOX genes are expressed in the limb buds but not the face (Figure 2D).…”
supporting
confidence: 84%
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“…However, no single clear candidate emerged that was expressed in all Coordinator-positive cell types and could explain the quantitative variation in Coordinator activity. Instead, every cell type expresses multiple HD TFs robustly, with groups of HDs showing overlapping expression in distinct regions of the developing face and limbs, consistent with their previously described association with specific positional identities [41][42][43] (such as along the anterior-posterior axis). For example and as expected, the ALX factors are enriched in the frontonasal prominence, which gives rise to the upper part of the face, whereas DLX factors are enriched in the mandibular prominence, which gives rise to the lower jaw, while the posterior HOX genes are expressed in the limb buds but not the face (Figure 2D).…”
supporting
confidence: 84%
“…The aforementioned tagging strategy did not significantly disrupt baseline TF levels; for TWIST1 and MSX1, protein levels actually increased upon tagging (Figure S3B). Based on previous studies 42,53 , we suspected ALX1 and ALX4 might have overlapping functions, so we generated multiple independent clonal lines with nonsense mutations in ALX4 on top of the ALX1 FV tagged background, as we were unable to degron-tag ALX4 (Figure 3C; Figure S3C).…”
Section: Multiple Homeodomains Co-bind Coordinator Motif With Twist1mentioning
confidence: 99%
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“…The high h 2 of the poll angle was consistent with results from a multi-breed genome-wide association study of the same joint angles from 300 FM and 224 Lipizzaner horse photographs [ 31 ]. The best-associated quantitative trait locus (QTL) was the poll angle on equine chromosome (ECA) 28, near the gene ALX1 , associated with cranial morphology [ 32 ]. The genome-wide h 2 for the poll angle in the two breeds was h 2 = 0.38, nearly equal to the pedigree-based h 2 estimated here.…”
Section: Discussionmentioning
confidence: 99%
“…More specifically, subcluster 2 displays a high level of expression of pharyngeal arch NCC mesenchyme marker Dlx2 (Figure 2-figure supplement 1) (Bulfone et al 1993). In contrast, subcluster 3 expresses a frontonasal mesenchyme marker Alx1 (Figure 2-figure supplement 1) (Iyyanar et al 2022). Consistent with these observations, neither population expresses a high level of neurogenic lineage markers such as Nrp1 and Nrp2, which is indicative of their undifferentiated state (Figure 2-figure supplement 1) (Lumb et al 2014).…”
Section: Resultsmentioning
confidence: 99%