Craniofacial Diseases Caused by Defects in Intracellular Trafficking

Cells use membrane-bound carriers to transport cargo molecules like membrane proteins and soluble proteins, to their destinations. Many signaling receptors and ligands are synthesized in the endoplasmic reticulum and are transported to their destinations through intracellular trafficking pathways. Some of the signaling molecules play a critical role in craniofacial morphogenesis. Not surprisingly, variants in the genes encoding intracellular trafficking machinery can cause craniofacial diseases. Despite the fundamental importance of the trafficking pathways in craniofacial morphogenesis, relatively less emphasis is placed on this topic, thus far. Here, we describe craniofacial diseases caused by lesions in the intracellular trafficking machinery and possible treatment strategies for such diseases.

A ROR2 coding variant is associated with craniofacial variation in domestic pigeons

SummaryVertebrate craniofacial morphogenesis is a highly orchestrated process that is directed by evolutionarily conserved developmental pathways 1,2. Within species, canalized developmental programs typically produce only modest morphological variation. However, as a result of millennia of artificial selection, the domestic pigeon (Columba livia) displays radical variation in craniofacial morphology within a single species. One of the most striking cases of pigeon craniofacial variation is the short beak phenotype, which has been selected in numerous breeds. Classical genetic experiments suggest that pigeon beak length is regulated by a small number of genetic factors, one of which is sex-linked (Ku2 locus) 3–5. However, the molecular genetic underpinnings of pigeon craniofacial variation remain unknown. To determine the genetic basis of the short beak phenotype, we used geometric morphometrics and quantitative trait loci (QTL) mapping on an F2 intercross between a short-beaked Old German Owl (OGO) and a medium-beaked Racing Homer (RH). We identified a single locus on the Z-chromosome that explains a majority of the variation in beak morphology in the RH x OGO F2 population. In complementary comparative genomic analyses, we found that the same locus is also strongly differentiated between breeds with short and medium beaks. Within the differentiated Ku2 locus, we identified an amino acid substitution in the non-canonical Wnt receptor ROR2 as a putative regulator of pigeon beak length. The non-canonical Wnt (planar cell polarity) pathway serves critical roles in vertebrate neural crest cell migration and craniofacial morphogenesis 6,7. In humans, homozygous ROR2 mutations cause autosomal recessive Robinow syndrome, a rare congenital disorder characterized by skeletal abnormalities, including a widened and shortened facial skeleton 8,9. Our results illustrate how the extraordinary craniofacial variation among pigeons can reveal genetic regulators of vertebrate craniofacial diversity.

The Fundamentals for Craniofacial Morphogenesis -A review with emphasis on the decisive dynamics

A rekindled need to widerstand details of craniofacial morphogenesis stems from the clinicians requirement to distinguish normal Variation from the effect of abnormal or pathologic processes. The understanding of the developmental blueprint is core to diagnosis, timing, planning of treatment and predicting post treatment outcomes. The morphogenesis works constantly towards a State of composite, architectonic balance among all of the separate growing parts. The various parts, developmentally merge into a functional whole with each part complementing the others as they all grow and function together. The present overview takes into account the principal fundamentals of the morphogenesis and the decisive dynamics involved therein. There is a cephalo-caudal gradient in the craniofacial growth pattern. In accordance with functional matrix theory, the major determinant of growth of maxilla and mandible is enlargement of nasal and oral cavities, which grow in response to functional needs. The craniofacial complex can be divided into four areas that grow rather differently.These are cranial vault, cranial base, nasomaxillary complex and mandible. The craniofacial morphogenesis leads to an aggregate State of structural and functional equilibrium. A thorough understanding of the process and patterns is the 'vital key' for successful therapies in this region.

An Eya1-Notch axis specifies bipotential epibranchial differentiation in mammalian craniofacial morphogenesis

Craniofacial morphogenesis requires proper development of pharyngeal arches and epibranchial placodes. We show that the epibranchial placodes, in addition to giving rise to cranial sensory neurons, generate a novel lineage-related non-neuronal cell population for mouse pharyngeal arch development. Eya1 is essential for the development of epibranchial placodes and proximal pharyngeal arches. We identify an Eya1-Notch regulatory axis that specifies both the neuronal and non-neuronal commitment of the epibranchial placode, where Notch acts downstream of Eya1 and promotes the non-neuronal cell fate. Notch is regulated by the threonine phosphatase activity of Eya1. Eya1 dephosphorylates p-threonine-2122 of the Notch1 intracellular domain (Notch1 ICD), which increases the stability of Notch1 ICD and maintains Notch signaling activity in the non-neuronal epibranchial placodal cells. Our data unveil a more complex differentiation program in epibranchial placodes and an important role for the Eya1-Notch axis in craniofacial morphogenesis.