Biology subjects

Lowery, L.

Publications and source records attributed to Lowery, L..

3 recordsLinked to original sources

bioRxiv2021

Tacc3 modulates microtubule network dynamicity and focal adhesion remodeling to affect cranial neural crest cell migration in Xenopus laevis

Coordinated cell migration is critical during embryogenesis, as cells must leave their point of origin, navigate a complex barrage of signals, and accurately position themselves to facilitate correct tissue and organ formation. The cell motility process relies on dynamic interactions of the F-actin and microtubule (MT) cytoskeletons. Our work focuses on how one MT plus-end regulator, Transforming Acidic Coiled-Coil 3 (Tacc3), can impact migration of cranial neural crest cells in Xenopus laevis. We previously demonstrated that tacc3 expression is expressed in cranial neural crest cells, and that Tacc3 can function as a MT plus-end tracking protein to regulate MT growth velocities. Here, we demonstrate that manipulation of Tacc3 protein levels is sufficient to alter cranial neural crest cell velocity in vitro. Tacc3 overexpression drives increased single-cell migration velocities, while Tacc3 KD results in reduced cell velocity and defective explant dispersion. We also show that Tacc3 can have spatially-enhanced effects on MT plus-end growth velocities as well as effects on focal adhesion remodeling. Together, we demonstrate that Tacc3 can facilitate neural crest cell motility through spatially-enhanced cytoskeletal remodeling, which may underlie the enhanced metastatic potential of Tacc3-overexpressing tumor cells.

cell biology↗

bioRxiv2020

16p12.1 deletion orthologs are expressed in motile neural crest cells and are important for regulating craniofacial development in Xenopus laevis

Copy number variants (CNVs) associated with neurodevelopmental disorders are characterized by extensive phenotypic heterogeneity. In particular, one CNV was identified in a subset of children clinically diagnosed with intellectual disabilities (ID) that results in a hemizygous deletion of multiple genes at chromosome 16p12.1. In addition to ID, individuals with this deletion display a variety of symptoms including microcephaly, seizures, cardiac defects, and growth retardation. Moreover, patients also manifest severe craniofacial abnormalities, such as micrognathia, cartilage malformation of the ears and nose, and facial asymmetries; however, the function of the genes within the 16p12.1 region have not been studied in the context of vertebrate craniofacial development. The craniofacial tissues affected in patients with this deletion all derive from the same embryonic precursor, the cranial neural crest, leading to the hypothesis that one or more of the 16p12.1 genes may be involved in regulating neural crest cell (NCC)-related processes. To examine this, we characterized the developmental role of the 16p12.1-affected gene orthologs, polr3e, mosmo, uqcrc2, and cdr2, during craniofacial morphogenesis in the vertebrate model system, Xenopus laevis. While the currently-known cellular functions of these genes are diverse, we find that they share similar expression patterns along the neural tube, pharyngeal arches, and later craniofacial structures. As these genes show co-expression in the pharyngeal arches where NCCs reside, we sought to elucidate the effect of individual gene depletion on craniofacial development and NCC migration. We find that reduction of several 16p12.1 genes significantly disrupts craniofacial and cartilage formation, pharyngeal arch migration, as well as NCC specification and motility. Thus, we have determined that some of these genes play an essential role during vertebrate craniofacial patterning by regulating specific processes during NCC development, which may be an underlying mechanism contributing to the craniofacial defects associated with the 16p12.1 deletion.

developmental biology↗

bioRxiv2020

Abelson-induced phosphorylation of TACC3 modulates its interaction with microtubules and affects its impact on axon outgrowth and guidance

Axon guidance is a critical process in forming the connections between a neuron and its target. The growth cone steers the growing axon towards the appropriate direction by integrating extracellular guidance cues and initiating intracellular signal transduction pathways downstream of these cues. The growth cone generates these responses by remodeling its cytoskeletal components. Regulation of microtubule dynamics within the growth cone is important for making guidance decisions. TACC3, as a microtubule plus-end binding protein, modulates microtubule dynamics during axon outgrowth and guidance. We have previously shown that embryos depleted of TACC3 displayed spinal cord axon guidance defects, while TACC3-overexpressing spinal neurons showed increased resistance to Slit2-induced growth cone collapse. Here, in order to investigate the mechanism behind TACC3-mediated axon guidance, we studied the importance of tyrosine phosphorylation induced by Abelson tyrosine kinase. We find that the phosphorylatable tyrosines within the TACC domain are important for the microtubule plus-end tracking behavior of TACC3. Moreover, TACC domain phosphorylation impacts axon outgrowth and guidance, and it also regulates microtubule extension into the growth cone periphery. Together, our results suggest that phosphorylation of TACC3 is a key regulatory mechanism by which TACC3 controls axon outgrowth and pathfinding decisions of neurons during embryonic development.

cell biology↗