Molecular Blueprint for Craniofacial Morphogenesis and Development

WIREs Developmental Biology

et al. 2017

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Craniofacial anomalies account for approximately one-third of all congenital birth defects reflecting the complexity of head and facial development. Craniofacial development is dependent upon a multipotent, migratory population of neural crest cells, which generate most of the bone and cartilage of the head and face. In this review, we discuss advances in our understanding of the pathogenesis of a specific array of craniofacial anomalies, termed facial dysostoses, which can be subdivided into mandibulofacial dysostosis, which present with craniofacial defects only, and acrofacial dysostosis, which encompasses both craniofacial and limb anomalies. In particular, we focus on Treacher Collins syndrome (TCS), Acrofacial Dysostosis-Cincinnati Type as well as Nager and Miller syndromes, and animal models that provide new insights into the molecular and cellular basis of these congenital syndromes. We emphasize the etiologic and pathogenic similarities between these birth defects, specifically their unique deficiencies in global processes including ribosome biogenesis, DNA damage repair, and pre-mRNA splicing, all of which affect neural crest cell development and result in similar tissue-specific defects.

Section: Introductionmentioning

confidence: 99%

Rare syndromes of the head and face: mandibulofacial and acrofacial dysostoses

Terrazas

Dixon

WIREs Developmental Biology

et al. 2017

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“…Their differentiation would therefore be primarily dependent upon intrinsic signals ( Bhatt et al, 2013 ). However as noted above, NCC exhibit varying degrees of cell fate potency, and therefore depend upon a combination of intrinsically expressed factors in concert with extrinsic signals emanating from the tissues they contact during their migration to undergo their proper spatiotemporal patterns of differentiation ( Trainor and Krumlauf, 2001 ; Trainor, 2003 , 2013 ; Trainor et al, 2003 ; Crane and Trainor, 2006 ). These key principles of NCC heterogeneity, potency, and plasticity which were determined through classic embryology, lineage tracing, and transplantation studies have been further substantiated by more recent genetic and molecular analyses such as single cell RNA-sequencing ( Morrison et al, 2017 ; Shang et al, 2018 ; Soldatov et al, 2019 ).…”

Section: Neural Crest Cell and Craniofacial Developmentmentioning

confidence: 99%

“…The vertebrate head and face comprise a complex assemblage of specialized tissues including the viscerocranium, chondrocranium and neurocranium, the central and peripheral nervous systems, and all of the major sense organs ( Trainor, 2013 ). The anatomical complexity of the craniofacial complex coupled with the initiation of its development during early embryogenesis renders the head and face prone to malformation.…”

Section: Introductionmentioning

confidence: 99%

Diabetes, Oxidative Stress, and DNA Damage Modulate Cranial Neural Crest Cell Development and the Phenotype Variability of Craniofacial Disorders

Fitriasari

2021

Front. Cell Dev. Biol.

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Craniofacial malformations are among the most common birth defects in humans and they often have significant detrimental functional, aesthetic, and social consequences. To date, more than 700 distinct craniofacial disorders have been described. However, the genetic, environmental, and developmental origins of most of these conditions remain to be determined. This gap in our knowledge is hampered in part by the tremendous phenotypic diversity evident in craniofacial syndromes but is also due to our limited understanding of the signals and mechanisms governing normal craniofacial development and variation. The principles of Mendelian inheritance have uncovered the etiology of relatively few complex craniofacial traits and consequently, the variability of craniofacial syndromes and phenotypes both within families and between families is often attributed to variable gene expression and incomplete penetrance. However, it is becoming increasingly apparent that phenotypic variation is often the result of combinatorial genetic and non-genetic factors. Major non-genetic factors include environmental effectors such as pregestational maternal diabetes, which is well-known to increase the risk of craniofacial birth defects. The hyperglycemia characteristic of diabetes causes oxidative stress which in turn can result in genotoxic stress, DNA damage, metabolic alterations, and subsequently perturbed embryogenesis. In this review we explore the importance of gene-environment associations involving diabetes, oxidative stress, and DNA damage during cranial neural crest cell development, which may underpin the phenotypic variability observed in specific craniofacial syndromes.

“…Ultimately the goal for managing any craniofacial anomaly continues to be prevention, but the development of therapeutics for minimizing or preventing craniofacial anomalies requires an understanding of the precise etiology and pathogenesis of individual malformation syndromes. Central to this is a better appreciation of the distinct signals, switches, and mechanism that regulate normal development of the head and neck [Trainor, 2013]. Achieving these goals involves a deeper understanding of the functional impact of genetic variants, both individually and in combination.…”

Section: Advances Inform Future Directionsmentioning

confidence: 99%

Facing up to the challenges of advancing Craniofacial Research

American J of Med Genetics Pt A

Richtsmeier

2015

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Craniofacial anomalies are among the most common human birth defects and have considerable functional, aesthetic, and social consequences. The early developmental origin as well as the anatomical complexity of the head and face render these tissues prone to genetic and environmental insult. The establishment of craniofacial clinics offering comprehensive care for craniofacial patients at a single site together with international research networks focused on the origins and treatment of craniofacial disorders has led to tremendous advances in our understanding of the etiology and pathogenesis of congenital craniofacial anomalies. However, the genetic, environmental, and developmental sources of many craniofacial disorders remain unknown. To overcome this problem and further advance craniofacial research, we must recognize current challenges in the field and establish priority areas for study. We still need (i) a deeper understanding of variation during normal development and within the context of any disorder, (ii) improved genotyping and phenotyping and understanding of the impact of epigenetics, (iii) continued development of animal models and functional analyses of genes and variants, and (iv) integration of patient derived cells and tissues together with 3D printing and quantitative assessment of surgical outcomes for improved practice. Only with fundamental advances in each of these areas will we be able to meet the challenge of translating potential therapeutic and preventative approaches into clinical solutions and reduce the financial and emotional burden of craniofacial anomalies.