What's retinoic acid got to do with it? Retinoic acid regulation of the neural crest in craniofacial and ocular development

Abstract

Vertebrate models, from zebrafish to mouse, and experimental tools, such as reporter transgenes, inhibitors of RA synthesis, and selective antagonists for RARs, have been successfully used to decipher retinoid functions during development at the cellular and molecular levels.Numerous examples from animal models and human diseases highlight the importance of RA in regulating neural crest contributions to craniofacial and ocular structures. The neural crest is a set of transient embryonic stem cells unique to vertebrates that originate at the border of the neural plate spanning the embryo from the diencephalon to the lumbosacral spinal cord. Neural crest cells undergo extensive and coordinated movements away from folds of the neural F I G U R E 1 Neural crest derivatives in the craniofacial region. (a) The neural crest is a transient population of embryonic stem cells that delaminate from the edge of the neural tube spanning from the diencephalon (Di) to the lumbosacral spinal cord (SpC). Neural crest cells that originate from the diencephalon and anterior mesencephalon (AM) migrate dorsal and ventral to the eye to populate the POM and frontonasal process (FNP). These cells migrate toward regions of high RA levels within the telencephalon (Te), POM, and frontonasal process. Neural crest cells from the posterior mesencephalon (PM) migrate into the first pharyngeal arch. Neural crest cells from the rhombencephalon, which are patterned by a RA gradient, migrate into the first through fourth pharyngeal arches in an anterior (AR) to posterior (PR) pattern. (b) The cranial neural crest is important in the development of the craniofacial skeleton. Neural crest cells in the frontonasal process give rise to the frontal bone (Fr), nasal bone (Na), and philtrum (Ph) in the midline of the face. The anterior portion of the first pharyngeal arch forms the maxillary (Mx) and zygomatic (Zy) bones while the posterior aspect gives rise to the mandible (Mn), The third and fourth pharyngeal arches both contribute to the hyoid (Ny) bone in the neck. (c) Neural crest cells, which are derived from the anterior mesenchyme and diencephalon, populate the periocular mesenchyme and migrate into the anterior segment of the eye. Ocular structures derived from the neural crest include the corneal stroma (CS), corneal endothelium (CEn), trabecular meshwork (TM), sclera (Scl), iris stroma (IS), uveal melanocytes (me), ciliary body muscle (CBM), and the tendons of the extraocular muscles (Tn). The corneal epithelium (CEp) and lens are derived from surface ectoderm while the ciliary body epithelium (CBE), retina (Ret), and retinal pigmented epithelium (RPE) arise from neuroepithelium. Schlemm's canal (SC) and extraocular muscles (EOM) originate from mesoderm. (d) Neural crest cells are also important in middle ear development. Vibrations are transmitted from the external ear, which consists of the pinna, auditory canal, and the tympanic membrane (Tym). The tympanic membrane is attached to the malleus in the middle ear. Both the malleus and the incus...

Zebrafish Models of Craniofacial Malformations: Interactions of Environmental Factors

“…Vitamin A is acquired through products such as meat, milk, eggs and carrots (Metzler and Sandell, 2016). Vitamin A deficiency (serum level < 0.70 µmol/L) is a public health concern in countries in Africa and South East Asia, and was associated with craniofacial malformations including CLP (WHO 4 ) (Ackermans et al, 2011;Mammadova et al, 2014;Metzler and Sandell, 2016;Williams and Bohnsack, 2019). Supplementation with vitamin A was associated with a lower cleft risk (OR = 0.48) (Johansen et al, 2008).…”

“…Use of acne medication that contains vitamin A derivatives during pregnancy may result in hypervitaminosis A. This increased the risk of craniofacial malformations including cleft lip, cleft palate, micrognathia and midface hypoplasia (Williams and Bohnsack, 2019).…”

The role of teratogens in neural crest development

“…Nevertheless, malformations in the central nervous system (holoprosencephaly, (Wals et al, ), the cranium, the face, the heart and the thymus of infants of topical‐retinoid‐exposed pregnant women have been reported in individual case reports (Lammer et al, ; Mondal, S, & Mishra, ). Additionally, as mentioned before, RA has been shown to be critical for NC formation (Williams & Bohnsack, ).…”

Regulating Retinoic Acid Availability during Development and Regeneration: The Role of the CYP26 Enzymes

“…Cardiac defects largely affect the formation/remodelling of the pharyngeal arch arteries into the great vessels and the development of the outflow and inflow tracts by addition of secondary heart field progenitors at the arterial and venous poles of the heart. Neural-crest driven septation of the outflow tract is also abnormal leading to CAT and aorticopulmonary windows [9,[76][77][78][79][80]101,[105][106][107][108][109], reviewed [10][11][12][13][14]110].…”