Understanding Cessation of Neural Crest Migration and Onset of Gangliogenesis

Citation

Urrutia, Hugo A. (2025) Understanding Cessation of Neural Crest Migration and Onset of Gangliogenesis. Dissertation (Ph.D.), California Institute of Technology. doi:10.7907/b31p-rp50. https://resolver.caltech.edu/CaltechTHESIS:04072025-220823071

Abstract

The neural crest is a multipotent, vertebrate-specific embryonic cell population that originates at the border of the developing central nervous system. Often referred to as the "fourth germ layer," the neural crest gives rise to diverse cell types, including craniofacial structures and components of the peripheral nervous system. Neural crest cells from specific axial levels in the embryo generate unique sets of progeny and migrate along distinct pathways, differing from those at other axial levels. During development, the formation of key structures within the vertebrate head, such as cranial ganglia and sense organs, requires coordinated migration and interactions between two distinct embryonic cell populations: the neural crest and the ectodermal placodes. The dual embryonic origin of cranial sensory ganglia has interested investigators for some time, yet surprisingly, little is still known about the neural crest–placode relationship. Despite extensive research, the process of cranial gangliogenesis, an intriguing example of how cell–cell interactions drive the assembly of complex structures in the developing embryo, remains incompletely understood. To address this gap, I aimed to advance our understanding of neural crest contributions to cranial sensory ganglia formation and investigate how interactions between these two distinct cell populations contribute to chick trigeminal gangliogenesis. To investigate this process, I focused on the early formation of the trigeminal ganglion, emphasizing on the transcriptional regulation of neural crest-derived cells. Using a combination of lineage labeling and in situ hybridization in chick embryos, we demonstrated that the transcription factor Tlx3 is expressed in neural crest-derived cells contributing to the cranial trigeminal ganglion, coinciding with the onset of ganglion condensation. Notably, loss-of-function experiments revealed that Tlx3 deficiency results in smaller ganglia with fewer neurons. Conversely, ectopic expression in migrating cranial neural crest cells accelerates neuronal differentiation, underscoring its critical role in neural crest-derived neuronal development. Taken together, these results demonstrate a pivotal role for Tlx3 in neural crest-derived cells during chick trigeminal gangliogenesis. As an additional candidate mediator, I investigated the potential role of Cxcl14. The concurrent expression of CXCL14 in placodal cells and its potential cognate receptor CXCR4 in neural crest cells raised the intriguing possibility that this ligand–receptor pair mediates signaling from placodal to neural crest cells, representing an additional form of their cell-cell interactions. Loss of Cxcl14 disrupts gangliogenesis and axonal projections, revealing an essential role for this chemokine in guiding neural crest-placode interactions during early ganglion formation. More specifically, perturbing Cxcl14 in the placodal population resulted in increased dispersion of neural crest-derived cells in the maxillomandibular lobe but not in the ophthalmic lobe of the trigeminal ganglion, highlighting its critical role in directing neural crest-placode interactions during early ganglion formation. In summary, the findings from my thesis advance our understanding of neural crest contributions to cranial sensory ganglia formation. By elucidating transcriptional and signaling mechanisms involved in trigeminal gangliogenesis, these results provide key insights into vertebrate neurodevelopment and lay the groundwork for further studies into neural crest biology.

Thesis Files