Exploring the developmental mechanisms underlying Wolf-Hirschhorn Syndrome: Evidence for defects in neural crest cell migration.

Wolf-Hirschhorn Syndrome (WHS) is a neurodevelopmental disorder characterized by mental retardation, craniofacial malformation, and defects in skeletal and heart development. The syndrome is associated with irregularities on the short arm of chromosome 4, including deletions of varying sizes and microduplications. Many of these genotypic aberrations in humans have been correlated with the classic WHS phenotype, and animal models have provided a context for mapping these genetic irregularities to specific phenotypes; however, there remains a significant knowledge gap concerning the cell biological mechanisms underlying these phenotypes. This review summarizes literature that has made recent contributions to this topic, drawing from the vast body of knowledge detailing the genetic particularities of the disorder and the more limited pool of information on its cell biology. Finally, we propose a novel characterization for WHS as a pathophysiology owing in part to defects in neural crest cell motility and migration during development.

The microtubule plus-end-tracking protein TACC3 promotes persistent axon outgrowth and mediates responses to axon guidance signals during development.

BACKGROUND: Formation of precise neuronal connections requires proper axon guidance. Microtubules (MTs) of the growth cone provide a critical driving force during navigation of the growing ends of axons. Pioneer MTs and their plus-end tracking proteins (+TIPs) are thought to play integrative roles during this navigation. TACC3 is a + TIP that we have previously implicated in regulating MT dynamics within axons. However, the role of TACC3 in axon guidance has not been previously explored. RESULTS: Here, we show that TACC3 is required to promote persistent axon outgrowth and prevent spontaneous axon retractions in embryonic Xenopus laevis neurons. We also show that overexpressing TACC3 can counteract the depolymerizing effect of low doses of nocodazole, and that TACC3 interacts with MT polymerase XMAP215 to promote axon outgrowth. Moreover, we demonstrate that manipulation of TACC3 levels interferes with the growth cone response to the axon guidance cue Slit2 ex vivo, and that ablation of TACC3 causes pathfinding defects in axons of developing spinal neurons in vivo. CONCLUSION: Together, our results suggest that by mediating MT dynamics, the + TIP TACC3 is involved in axon outgrowth and pathfinding decisions of neurons during embryonic development.

Xenopus TACC2 is a microtubule plus end-tracking protein that can promote microtubule polymerization during embryonic development.

Microtubule dynamics is regulated by plus end-tracking proteins (+TIPs), which localize to the plus ends of microtubules (MTs). We previously showed that TACC1 and TACC3, members of the transforming acidic coiled-coil protein family, can act as +TIPs to regulate MT dynamics in Xenopus laevis Here we characterize TACC2 as a +TIP that localizes to MT plus ends in front of EB1 and overlapping with TACC1 and TACC3 in multiple embryonic cell types. We also show that TACC2 can promote MT polymerization in mesenchymal cells but not neuronal growth cones, thus displaying cell-type specificity. Structure-function analysis demonstrates that the C-terminal region of TACC2 is both necessary and sufficient to localize to MT plus ends and promote increased rates of MT polymerization, whereas the N-terminal region cannot bind to MT plus ends but can act in a dominant-negative capacity to reduce polymerization rates. Finally, we analyze mRNA expression patterns in Xenopus embryos for each TACC protein and observe neural enrichment of TACC3 expression compared with TACC1 and TACC2, which are also expressed in mesodermal tissues, including somites. Overall these data provide a novel assessment of all three TACC proteins as a family of +TIPs by highlighting the unique attributes of each, as well as their collective characteristics.

TACC3 is a microtubule plus end-tracking protein that promotes axon elongation and also regulates microtubule plus end dynamics in multiple embryonic cell types.

Microtubule plus end dynamics are regulated by a conserved family of proteins called plus end-tracking proteins (+TIPs). It is unclear how various +TIPs interact with each other and with plus ends to control microtubule behavior. The centrosome-associated protein TACC3, a member of the transforming acidic coiled-coil (TACC) domain family, has been implicated in regulating several aspects of microtubule dynamics. However, TACC3 has not been shown to function as a +TIP in vertebrates. Here we show that TACC3 promotes axon outgrowth and regulates microtubule dynamics by increasing microtubule plus end velocities in vivo. We also demonstrate that TACC3 acts as a +TIP in multiple embryonic cell types and that this requires the conserved C-terminal TACC domain. Using high-resolution live-imaging data on tagged +TIPs, we show that TACC3 localizes to the extreme microtubule plus end, where it lies distal to the microtubule polymerization marker EB1 and directly overlaps with the microtubule polymerase XMAP215. TACC3 also plays a role in regulating XMAP215 stability and localizing XMAP215 to microtubule plus ends. Taken together, our results implicate TACC3 as a +TIP that functions with XMAP215 to regulate microtubule plus end dynamics.