PHACES Syndrome: From the Brain to the Face via the Neural Crest Cells

Mesenchephalic and rhombencephalic neural crest cells generate the craniofacial skeleton, special sensory organs, and subsets of cranial sensory receptor neurons. They do so while preserving the anterior-posterior (A-P) identity of their neural tube origins. This organizational principle is paralleled by central nervous system circuits that receive and process information from facial structures whose A-P identity is in register with that in the brain. Prior to morphogenesis of the face and its circuits, however, neural crest cells act as “inductive ambassadors” from distinct regions of the neural tube to induce differentiation of target craniofacial domains and establish an initial interface between the brain and face. At every site of bilateral, non-axial secondary induction, neural crest constitutes all or some of the mesenchymal compartment for non-axial mesenchymal/epithelial (M/E) interactions. Thus, for epithelial domains in the craniofacial primordia, aortic arches, limbs, the spinal cord, and the forebrain (Fb), neural crest-derived mesenchymal cells establish local sources of inductive signaling molecules that drive morphogenesis and cellular differentiation. This common mechanism for building brains, faces, limbs, and hearts, A-P axis specified, neural crest-mediated M/E induction, coordinates differentiation of distal structures, peripheral neurons that provide their sensory or autonomic innervation in some cases, and central neural circuits that regulate their behavioral functions. The essential role of this neural crest-mediated mechanism identifies it as a prime target for pathogenesis in a broad range of neurodevelopmental disorders. Thus, the face and the brain “predict” one another, and this mutual developmental relationship provides a key target for disruption by developmental pathology.

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Jaw and branchial arch mutants in zebrafish I: branchial arches

Development ◽

10.1242/dev.123.1.329 ◽

1996 ◽

Vol 123 (1) ◽

pp. 329-344 ◽

Cited By ~ 21

Author(s):

T.F. Schilling ◽

T. Piotrowski ◽

H. Grandel ◽

M. Brand ◽

C.P. Heisenberg ◽

...

Keyword(s):

Neural Crest ◽

Zebrafish Embryo ◽

Neural Crest Cells ◽

Branchial Arch ◽

Pigment Cells ◽

Pharyngeal Arches ◽

Pectoral Fins ◽

Branchial Arches ◽

Group Members ◽

The Brain

Jaws and branchial arches together are a basic, segmented feature of the vertebrate head. Seven arches develop in the zebrafish embryo (Danio rerio), derived largely from neural crest cells that form the cartilaginous skeleton. In this and the following paper we describe the phenotypes of 109 arch mutants, focusing here on three classes that affect the posterior pharyngeal arches, including the hyoid and five gill-bearing arches. In lockjaw, the hyoid arch is strongly reduced and subsets of branchial arches do not develop. Mutants of a large second class, designated the flathead group, lack several adjacent branchial arches and their associated cartilages. Five alleles at the flathead locus all lead to larvae that lack arches 4–6. Among 34 other flathead group members complementation tests are incomplete, but at least six unique phenotypes can be distinguished. These all delete continuous stretches of adjacent branchial arches and unpaired cartilages in the ventral midline. Many show cell death in the midbrain, from which some neural crest precursors of the arches originate. lockjaw and a few mutants in the flathead group, including pistachio, affect both jaw cartilage and pigmentation, reflecting essential functions of these genes in at least two neural crest lineages. Mutants of a third class, including boxer, dackel and pincher, affect pectoral fins and axonal trajectories in the brain, as well as the arches. Their skeletal phenotypes suggest that they disrupt cartilage morphogenesis in all arches. Our results suggest that there are sets of genes that: (1) specify neural crest cells in groups of adjacent head segments, and (2) function in common genetic pathways in a variety of tissues including the brain, pectoral fins and pigment cells as well as pharyngeal arches.

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The developmental fate of the cephalic mesoderm in quail-chick chimeras

Development ◽

10.1242/dev.114.1.1 ◽

1992 ◽

Vol 114 (1) ◽

pp. 1-15 ◽

Cited By ~ 35

Author(s):

G.F. Couly ◽

P.M. Coltey ◽

N.M. Le Douarin

Keyword(s):

Neural Crest ◽

Neural Crest Cells ◽

Paraxial Mesoderm ◽

Avian Embryo ◽

Facial Skeleton ◽

Developmental Fate ◽

Prechordal Mesoderm ◽

The Face ◽

Neural Crest Origin ◽

Neurula Stage

The developmental fate of the cephalic paraxial and prechordal mesoderm at the late neurula stage (3-somite) in the avian embryo has been investigated by using the isotopic, isochronic substitution technique between quail and chick embryos. The territories involved in the operation were especially tiny and the size of the transplants was of about 150 by 50 to 60 microns. At that stage, the neural crest cells have not yet started migrating and the fate of mesodermal cells exclusively was under scrutiny. The prechordal mesoderm was found to give rise to the following ocular muscles: musculus rectus ventralis and medialis and musculus oblicus ventralis. The paraxial mesoderm was separated in two longitudinal bands: one median, lying upon the cephalic vesicles (median paraxial mesoderm—MPM); one lateral, lying upon the foregut (lateral paraxial mesoderm—LPM). The former yields the three other ocular muscles, contributes to mesencephalic meninges and has essentially skeletogenic potencies. It contributes to the corpus sphenoid bone, the orbitosphenoid bone and the otic capsules; the rest of the facial skeleton is of neural crest origin. At 3-somite stage, MPM is represented by a few cells only. The LPM is more abundant at that stage and has essentially myogenic potencies with also some contribution to connective tissue. However, most of the connective cells associated with the facial and hypobranchial muscles are of neural crest origin. The more important result of this work was to show that the cephalic mesoderm does not form dermis. This function is taken over by neural crest cells, which form both the skeleton and dermis of the face. If one draws a parallel between the so-called “somitomeres” of the head and the trunk somites, it appears that skeletogenic potencies are reduced in the former, which in contrast have kept their myogenic capacities, whilst the formation of skeleton and dermis has been essentially taken over by the neural crest in the course of evolution of the vertebrate head.

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Craniofacial growth and development

Paediatric Dentistry ◽

10.1093/oso/9780198789277.003.0009 ◽

2018 ◽

Author(s):

T.J. Gillgrass ◽

R. Welbury

Keyword(s):

Neural Crest ◽

Cleft Lip ◽

Neural Crest Cells ◽

Signs And Symptoms ◽

Postnatal Growth ◽

Prenatal Development ◽

Routine Care ◽

Developing Heart ◽

Frontal Process ◽

The Face

This chapter describes, in general terms, the prenatal development and postnatal growth of the craniofacial skeleton, and the occlusal development of the primary and permanent dentitions. Understanding of embryological development is essential for the dental practitioner who may frequently face patients with common craniofacial anomalies such as cleft lip and/or palate. For routine care, an understanding of their development and aetiology will bring insight to their likely presenting signs and symptoms. This section will include a brief summary of the development of the face, including the neural crest and pharyngeal arches. It is not the intention of this summary to be in any way a complete or thorough description but simply to describe some of the key cells/interactions and structures. Neural crest cells are derived from the neural fold, and are highly migratory and specialized cells capable of predetermined differentiation. The differentiation occurs after their migration and is essential for the normal development of face and teeth. By week 4 the primitive mouth or stomatodeum is bordered laterally and from the developing heart inferiorly by the pharyngeal or branchial arches. These are six bilateral cylindrical thickenings (although the fifth and sixth are small) which form in the pharyngeal wall and into which the neural crest cells migrate. They are separated externally by the branchial grooves and internally by the pharyngeal pouches. The first groove and pouches are involved in the formation of the auditory apparatus and the Eustachian tube. Each arch has a derived cartilage rod, muscular, nervous, and vascular component. The first two arches and their associated components are central to the development of the facial structures. This period is also characterized by the development of the organs for hearing, sight, and smell, namely the otic, optic, and nasal placodes. By the end of week 4, thickenings start to develop in the frontal process. The medial and lateral frontonasal processes develop from these, together with the nasal placodes. The maxillary process develops from the first pharyngeal arch and grows forward to meet the medial and nasal processes, from which it is separated by distinct grooves at week 7.

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Embryology of the head and neck

10.1093/med/9780198767831.003.0015 ◽

2021 ◽

pp. 519-536

Author(s):

Daniel R. van Gijn ◽

Jonathan Dunne

Keyword(s):

Neural Crest ◽

Head And Neck ◽

Cell Population ◽

Endochondral Ossification ◽

Developing Brain ◽

Intramembranous Ossification ◽

Pharyngeal Arches ◽

The Face ◽

Base Of The Skull ◽

The Brain

Development of the head is dominated by the changing shape of the brain and the formation of pharyngeal arches through which blood from the ventrally placed heart can pass to the dorsal aorta. The origin of the cell population within the head and neck is important as it predicts the behaviour and attributes of the cells and their progeny. The neural crest gives rise to an extensive mesenchymal population which contributes to the skull and enters and patterns the pharyngeal arches. The skull (neurocranium) forms around the developing brain and its emerging nerves. The base of the skull forms initially in cartilage (endochondral ossification) and the vault forms from neural crest mesenchyme (intramembranous ossification). The face and jaws (viscerocranium) form around the developing pharynx from a series of pharyngeal arches (numbered 1,2,3,4 and 6) which pass from the lateral sides of the pharynx to meet ventromedially.

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Snrpb, the gene mutated in CCMS, is haploinsufficient and required in neural crest cells for proper splicing of developmentally important genes essential for craniofacial morphogenesis

10.1101/2021.08.07.455514 ◽

2021 ◽

Author(s):

Sabrina Shameen Alam ◽

Shruti Kumar ◽

Marie-Claude Beauchamp ◽

Eric Bareke ◽

Alexia Boucher ◽

...

Keyword(s):

Neural Crest ◽

Target Genes ◽

Intron Retention ◽

Exon Skipping ◽

Neural Crest Cells ◽

Heterozygous Deletion ◽

Craniofacial Malformations ◽

Pharyngeal Arches ◽

The Face ◽

Morphological Defects

Heterozygous mutations in SNRPB, an essential core component of the five small ribonucleoprotein particles of the spliceosome, are responsible for Cerebrocostomandibular Syndrome (CCMS). However, the underlying pathophysiology of CCMS remains a mystery. We generated mouse embryos with heterozygous deletion of Snrpb and showed that they arrest shortly after implantation. We also showed that heterozygous deletion of Snrpb in the developing brain and neural crest cells models many of the craniofacial malformations found in CCMS, and results in death shortly after birth. Abnormalities in these mutant embryos ranged from cleft palate to a complete absence of the ventral portion of the face and are due to apoptosis of the neural crest cells in the frontonasal prominence and pharyngeal arches. RNAseq analysis of mutant embryonic heads prior to morphological defects revealed increased exon-skipping and intron-retention in association with increased 5' splice strength. Mutant embryonic heads had increased exon-skipping in Mdm2 and Mdm4 negative regulators of the P53-pathway and a increased nuclear P53 and P53-target genes. However, removing one or both copies of P53 in Snrpb heterozygous mutant neural crest cells did not rescue craniofacial development. We also found a small but significant increase in exon-skipping of several transcripts required for head and midface development, including Smad2 and Rere. Furthermore, mutant embryos exhibited ectopic or missing expression of Fgf8 and Shh, which are required to coordinate face and brain development. Thus, we propose that mis-splicing of transcripts that regulate P53-activity and craniofacial-specific genes both contribute to craniofacial malformations.

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Analysis of neural crest–derived clones reveals novel aspects of facial development

Science Advances ◽

10.1126/sciadv.1600060 ◽

2016 ◽

Vol 2 (8) ◽

pp. e1600060 ◽

Cited By ~ 29

Author(s):

Marketa Kaucka ◽

Evgeny Ivashkin ◽

Daniel Gyllborg ◽

Tomas Zikmund ◽

Marketa Tesarova ◽

...

Keyword(s):

Neural Crest ◽

Neural Crest Cells ◽

Limb Bud ◽

Cellular Mechanisms ◽

Facial Region ◽

Mouse Mutants ◽

The Face ◽

Analysis Computer ◽

Cranial Neural Crest Cells ◽

Facial Development

Cranial neural crest cells populate the future facial region and produce ectomesenchyme-derived tissues, such as cartilage, bone, dermis, smooth muscle, adipocytes, and many others. However, the contribution of individual neural crest cells to certain facial locations and the general spatial clonal organization of the ectomesenchyme have not been determined. We investigated how neural crest cells give rise to clonally organized ectomesenchyme and how this early ectomesenchyme behaves during the developmental processes that shape the face. Using a combination of mouse and zebrafish models, we analyzed individual migration, cell crowd movement, oriented cell division, clonal spatial overlapping, and multilineage differentiation. The early face appears to be built from multiple spatially defined overlapping ectomesenchymal clones. During early face development, these clones remain oligopotent and generate various tissues in a given location. By combining clonal analysis, computer simulations, mouse mutants, and live imaging, we show that facial shaping results from an array of local cellular activities in the ectomesenchyme. These activities mostly involve oriented divisions and crowd movements of cells during morphogenetic events. Cellular behavior that can be recognized as individual cell migration is very limited and short-ranged and likely results from cellular mixing due to the proliferation activity of the tissue. These cellular mechanisms resemble the strategy behind limb bud morphogenesis, suggesting the possibility of common principles and deep homology between facial and limb outgrowth.

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Nervous System Embriology

International Journal of Medical and Surgical Sciences ◽

10.32457/ijmss.2015.004 ◽

2018 ◽

Vol 2 (1) ◽

pp. 385-400

Author(s):

Ángel Rodríguez ◽

Susana Domínguez ◽

Mario Cantín ◽

Mariana Rojas

Keyword(s):

Nervous System ◽

Neural Crest ◽

Functional Organization ◽

Neural Crest Cells ◽

Tube Formation ◽

Neural Plate ◽

Sensory Ganglia ◽

Final Development ◽

System 1 ◽

The Brain

This study briefly reviews the main events and processes that lead to the formation of the nervous system in mammals. At the end of gastrulation, they begin a series of fundamental morphogenetic processes with the formation of the neural plate (start of neurulation) culminating in the attainment of a normal nervous system. Embryological ectodermal primordia involved in the formation of the nervous system are the neuroectoblast, the neural crest cells and placodes that will evolve based on inductive phenomena, mainly from the notochord, prechordal plate and ectoderm. During the embryonic period consolidates the final development plan of the nervous system: 1) it comes complete neural tube formation when closing the rostral and caudal neuropores, 2) the different placodes invaginate to help form the organs of senses and sensory ganglia of the head, 3) the neural crest cells migrate to give rise to sensory and autonomic constituents of the peripheral nervous system and 4) developing brain vesicles, which will derive all the constituents of the brain. In the fetal period nervous system increases its mass and ultimately strengthens their functional organization.

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