Embryonic Developmental Disruptions via Centriole Inhibition

Abstract

The centriole, a key organelle for cell division and ciliogenesis, is indispensable for embryonic development. The advent of specific pharmacological inhibitors targeting distinct stages of centriole biogenesis—so-called “centriole blockers”—has provided powerful tools to dissect its spatiotemporal functions. This review synthesizes findings from experimental models (mouse, zebrafish, Xenopus, and human stem cell-derived organoids) exposed to three major inhibitor classes: specific PLK4 inhibitors (e.g., centrinone), centriole assembly disruptors (e.g., Bril), and multi-kinase inhibitors (e.g., CFI-400945). Our comparative meta-analysis reveals a fundamental dichotomy in developmental disruption mechanisms. PLK4 inhibition primarily triggers p53-dependent apoptotic depletion of rapidly proliferating progenitors, modeling microcephaly and causing pre-implantation arrest. In contrast, assembly inhibitors predominantly cause structural ciliary defects, disrupting Sonic Hedgehog and Wnt signaling to produce classic ciliopathy phenotypes (polydactyly, renal cysts, laterality defects). The multi-kinase inhibitor CFI-400945 demonstrates compounded toxicity from off-target effects. These phenotypes directly mirror human “centriolopathies,” including autosomal recessive primary microcephaly (MCPH) and syndromic ciliopathies (e.g., Meckel-Gruber syndrome), validating the pathological mechanisms. The analysis establishes the embryo's extreme vulnerability to “centriolar stress,” where checkpoints eliminate defective cells, and highlights the dual role of the centriole as both a mitotic licensor and a ciliary organizer. These insights carry significant translational implications, warning of high teratogenic risk for anticancer therapies targeting this pathway while endorsing these inhibitors as precise tools for disease modeling and therapeutic screening.