Cranial ganglia of the peripheral nervous system are critical for integrating sensory information and controlling cell movements. The appropriate coalescence of both neural crest cells (NCCs) and placode cells (PCs) is required for the proper formation of many of these ganglia. Migratory NCCs also differentiate to create other cell types, including the craniofacial skeleton and skin pigment cells. Abnormalities that occur during NCC and PC development are thus directly responsible for many human congenital and hereditary malformations, diseases and cancers. Cranial ganglia assembly involves the creation of new junctions between NCCs and PCs, facilitating their interactions with one another and with their surroundings, but the molecular composition of these junctional complexes is not known. Our published and preliminary data indicate that NCCs and PCs each express a different repertoire of cadherins and catenins, which may function to mediate both NCC and PC migration as well as the formation of novel heterophilic adherens junctions between NCCs and PCs during cranial ganglia assembly. Such heterophilic interactions have not been reported between different cell types, and, together with data on other junctions, could prove to be paradigm-shifting in defining how different cells coalesce to form multi-cellular structures. Moreover, we report for the first time the effects of perturbation of gap junctions, which play crucial roles in cell-cell communication, on chick NCC migration. In light of our data, we hypothesize that cranial ganglia assembly is dependent upon the temporal formation of heterophilic cadherin-based adherens junctions between migratory NCCs and PCs, followed by the creation of other anchoring and communicating junctions.
The Specific Aims of this application are to: 1) determine the requirement for cadherins and catenins in mediating NCC and PC migration, 2) define the role of cadherins and catenins in cranial ganglia formation, and 3) define additional junctional complexes that orchestrate cranial gangliogenesis.
In Aim 1, we will perturb NCC and PC cadherins and catenins by adapting the use of photo morpholinos and inducible expression constructs to the chick embryo and documenting changes in NCC and PC migration through in vitro and in vivo imaging assays.
In Aim 2, we will use the above perturbation methods and biochemical assays we have pioneered in the chick embryo to evaluate the function of cadherins and catenins, and heterophilic interactions, in cranial ganglia assembly.
In Aim 3, we will perform RNA-sequencing of chick trigeminal ganglia to elucidate a molecular signature for gangliogenesis, facilitating the identification of other junctional complexes that mediate NCC-PC interactions. The proposed research is innovative because it takes a multi-disciplinary approach that combines embryology, biochemistry, and cell and molecular biology to examine how different cell populations interact during tissue formation. These studies are significant because the results will enhance our understanding of the mechanisms underlying the intercellular interactions required to create tissues and organs and could lead to the development of new treatments for human diseases.
The proposed research is relevant to public health because of the biological significance and contribution of the neural crest to the proper formation of human bodies, such as the bones of the face, nerves, skin pigment cells, and parts of the heart. How neural crest cells become such diverse structures can help us comprehend what happens when neural crest development is impaired, and human syndromes, disease, and cancers arise. Thus, the proposed research is directly relevant to NIH's mission to understand the fundamental processes controlling development and the use of that knowledge to improve overall human health and quality of life.
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