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A Twist1-regulated distal enhancer crucial for Alx1 gene expression and function during craniofacial development
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DOI：10.1016/j.ydbio.2026.03.008.png)
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Abstract
En 中文
Disruption of ALX1 causes frontonasal dysplasia syndrome-3, characterized by extreme microphthalmia, severe midfacial hypoplasia, and orofacial clefting. Recent studies have revealed critical tissue-specific roles of ALX1 in patterning both cranial mesoderm and cranial neural crest-derived facial mesenchyme. However, the molecular mechanisms regulating Alx1 gene expression during craniofacial development are largely unknown. In this study, we have identified a distal enhancer (Alx1-DE1) residing in a large intron of the neighboring Lrriq1 gene and demonstrate that deletion of this enhancer specifically affects Alx1 gene expression in the cranial neural crestderived frontonasal mesenchyme and causes frontonasal and ocular defects partly phenocopying Alx1-deficient mice. We further functionally analyzed four evolutionary conserved regions, ECR1 - ECR4, in the Alx1-DE1 enhancer. Remarkably, ECR1, whose homologous region in the human genome harbors a lead single nucleotide variation significantly associated with facial and cranial vault shape differences, exhibits high enrichment of Twist1 transcription factor occupancy in mouse embryonic frontonasal tissues and drove Twist1-dependent reporter transgene expression specifically in the developing periocular and frontonasal mesenchyme in transgenic mice. These results reveal Alx1-DE1 as a crucial tissue-specific enhancer through which Twist1 and other major craniofacial developmental regulators control craniofacial patterning and morphogenesis.
Keywords:
Craniofacial
Enhancer
Frontonasal dysplasia
Neural crest
Alx1
Twist1
Journal
IF:
2.1
Papers:
393
Citations:
2.2W
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