Mechanisms that Regulate the Development and Evolution of Craniofacial Laterality.
Lateralization of the vertebrate body plan is both evolutionarily conserved and developmentally rigid. Conspicuous left-right (LR) asymmetries are evident in a variety of tissues, including the brain, heart, lungs and gut. However, accumulating evidence suggests that LR positional identity also exist in superficially paired structures, raising the interesting question of whether asymmetry may be the default state during vertebrate development. Support for this hypothesis comes from a wide range of disciplines, including human genetics, experimental embryology, and evolution. From a clinical perspective a multitude of human birth defects are characterized by asymmetries in superficially paired organs (e.g., hemifacial microsomia, Treacher-Collins syndrome, hemihypertrophy). Here, spontaneous or inherited defects in the developmental program lead to an accentuation of laterality. Evidence of latent craniodental handedness also comes from nature, where a multitude of vertebrate taxa have elaborated asymmetries along the LR axis in the head. Perhaps the most striking example of craniofacial asymmetry in nature comes from narwals, where the left incisor in males grows up to 10 feet in length. Odontocete whales also exhibit pronounced skull asymmetries associated with echolocation. Flatfish display dramatic morphological and functional asymmetries, which are modifications for specialized prey-capture behaviors. Finally, a clade of cichlid fishes from Lake Tanganyika has evolved craniodental asymmetries to more effectively strip scales from the left or right flank of prey species (see below).
Examples of asymmetry in nature. From left to right: heart, visceral organs, brain, clinical facial asymmetry, narwal tooth, odontocete whale skull.
Taken together, these observations suggest that the vertebrate body plan is only superficially bilaterally symmetrical, and that handedness is inherent to most if not all paired structures. One of the foci of our lab is to reveal the mechanisms that regulate craniodental laterality.
The left-right machinery.
In vertebrates, the earliest mechanism that participates in the establishment of the LR axis involves H+/K+ -ATPase activity during early cleavage stages. Even at this early stage (before the onset of zygote transcription) the embryo knows its left from right. During late gastrulation and early somitogenesis stages, laterality information is transferred to the Notch signaling cascade, which is required to maintain proper asymmetric expression of nodal in the lateral plate mesoderm (LPM). H+/K+ -ATPase activity mediates Notch signaling through asymmetric concentrations of extracellular Ca+ around the node.
A parallel asymmetric pathway involves directed ciliary movement within the node, which is also required for proper asymmetric expression of nodal in the LPM. The asymmetric functions of ciliary movement and Notch signaling occur at approximately the same time, and both target downstream nodal expression. However, the available evidence suggests that these two mechanisms are independent of one another.
The collective activities of H+/K+ -ATPase-Notch and the ciliated node relay laterality information from the embryonic midline to the left LPM via nodal signaling, which in turn directs proper asymmetric development of the heart, viscera and brain. We want to understand how these pathways affect laterality of superficially paired structures (i.e., the craniofacial skeleton).
Factors required to maintain bilateral symmetry.
Experimentally induced mutations can also lead to pronounced asymmetric development of normally paired structures. We have recently shown that zebrafish lacking fgf8 exhibit conspicuous craniofacial asymmetries, characterized by skeletal elements missing from the right side of the pharynx.
Asymmetric development of the pharyngeal skeleton in ace/fgf8 mutants. Mutant larvae have fewer pharyngeal cartilages on the right side of the pharynx.
It has also been shown that zebrafish lacking retinoic acid (RA) exhibit asymmetric somite development. In both fgf8 and RA deficient mutants, asymmetric defects were linked to the presence and proper function of Kupffer’s vesicle, a ciliated node that mediates laterality information in zebrafish. These observations are consistent with a model where Fgf and RA signaling act to buffer the pharynx and somites from the lateralizing effects of Kupffer’s vesicle, leading to bilaterally symmetric development of these structures.
Most laterality studies assume that symmetry is the default condition, and seek to understand how asymmetries develop (i.e., in the viscera and brain). But what if we flip the current paradigm? What if the embryonic body plan (or at least the craniofacial skeleton) is, in fact, inherently asymmetric? With this perspective the question becomes, how does symmetrical development occur within an asymmetric environment? We are addressing this question as it pertains to the craniofacial and appendicular skeleton.
What are the laterality mechanisms targeted by natural selection?
A classic example of frequency-dependent natural selection comes from Lake Tanganyika’s scale eating cichlids, where the frequency of individuals with left- and right-handed jaws fluctuates over time. While the jaw asymmetry itself is likely polygenic, handedness in scale eating cichlids exhibits a simple Mendelian one locus, two allele mode of inheritance. Asymmetries in cichlid jaw morphology are also linked to a behavioral asymmetry, with left-handed morphs attacking the right flank of prey species and right-handed morphs attacking the left flank.
The scale eating cichlid, Perissodus microlepis, exhibits a left- and right-handed morph, which is evident early in development.
We want to understand the genetic and developmental basis of craniofacial laterality in African scale eating cichlids.
Specific areas of research:
If you are interested in participating in one or more of these projects please contact me: rcalbert@syr.edu
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