Retinoic Acid Deficiency Underlies the Etiology of Midfacial Defects

Abstract

Embryonic craniofacial development depends on the coordinated outgrowth and fusion of multiple facial primordia, which are populated with cranial neural crest cells and covered by the facial ectoderm. Any disturbance in these developmental events, their progenitor tissues, or signaling pathways can result in craniofacial deformities such as orofacial clefts, which are among the most common birth defects in humans. In the present study, we show that Rdh10 loss of function leads to a substantial reduction in retinoic acid (RA) signaling in the developing frontonasal process during early embryogenesis, which results in a variety of craniofacial anomalies, including midfacial cleft and ectopic chondrogenic nodules. Elevated apoptosis and perturbed cell proliferation in postmigratory cranial neural crest cells and a substantial reduction in Alx1 and Alx3 transcription in the developing frontonasal process were associated with midfacial cleft in Rdh10-deficient mice. More important, expanded Shh signaling in the ventral forebrain, as well as partial abrogation of midfacial defects in Rdh10 mutants via inhibition of Hh signaling, indicates that misregulation of Shh signaling underlies the pathogenesis of reduced RA signaling-associated midfacial defects. Taken together, these data illustrate the precise spatiotemporal function of Rdh10 and RA signaling during early embryogenesis and their importance in orchestrating molecular and cellular events essential for normal midfacial development.

Frem1 activity regulated by Sonic Hedgehog signaling in the cranial neural crest mesenchyme guides midfacial morphogenesis

“…cNCCs are specified at the dorsal margins of the anterior neural folds, undergo epithelial-to-mesenchymal transition, migrate extensively, and then rapidly proliferate to form the majority of the connective tissue of the head and face. Disruptions in cNCC migration and proliferation contribute to facial malformations and dysmorphology [11; 54]. While not impacting cNCC migration, we found that addition of FREM1 to cNCCs resulted in a concentration-dependent increase in proliferation (Fig.…”

Frem1 activity is regulated by Sonic hedgehog signaling in the cranial neural crest mesenchyme during midfacial morphogenesis

“…cNCCs are specified at the dorsal margins of the anterior neural folds, undergo epithelial‐to‐mesenchymal transition, migrate extensively, and then rapidly proliferate to form the majority of the connective tissue of the head and face. Disruptions in cNCC migration and proliferation contribute to facial malformations and dysmorphology 48,49 . While not overtly impacting cNCC migration in the scratch assay, we found that addition of FREM1 to cNCCs resulted in a concentration‐dependent increase in proliferation (Figure 5).…”

“…Disruptions in cNCC migration and proliferation contribute to facial malformations and dysmorphology. 48,49 While not overtly impacting cNCC migration in the scratch assay, we found that addition of FREM1 to cNCCs resulted in a concentration-dependent increase in proliferation (Figure 5). The concentration-dependence of this effect is notable given the regulation of Frem1 by a secreted morphogen and the spatial gradient of Frem1 expression during facial morphogenesis.…”

Osteoblastic RAR Inhibition Causes VAD-Like Craniofacial Skeletal Deformity

“…Doctors have noticed that maternal VAD patients presented with microphthalmia, blindness (Chakraborty and Chandra 2021), and bone deformities, which could result in morbidity (Williams and Bohnsack 2019). Several genetic RA deficiency models that were constructed have exhibited midfacial cleft (Wu et al 2022), nasal abnormality, and eye defects (Duester 2008). Nevertheless, although VAD patients showed an induction in the risk of osteopenia, osteoporosis, and severe craniofacial skeletal disorders (Conaway et al 2013), how retinoid signaling regulates craniofacial bone development and metabolism remains unclear, as well as the pathogenesis of VAD craniofacial skeletal deformity.…”