Centriole Biology: From Duplication to Ciliogenesis

Centrioles are essential organelles that organize microtubules within the cell, playing critical roles in cell division, ciliogenesis, and intracellular transport. Defects in their formation or function can lead to severe cellular disorders.

Understanding how centrioles duplicate, participate in mitosis, and contribute to cilia formation provides key insights into cell biology.

Structure And Core Components

Centrioles are cylindrical structures composed primarily of microtubules, forming a scaffold that supports their diverse functions. Each centriole consists of nine triplet microtubules arranged in radial symmetry, creating a rigid yet dynamic framework. This organization allows them to serve as microtubule-organizing centers within the centrosome, aiding in mitotic spindle formation and intracellular transport. The triplet microtubules are stabilized by associated proteins, including centrin, SAS-6, and CEP135, which regulate assembly and maintain structural integrity.

Beyond microtubules, centrioles incorporate accessory proteins that dictate their function and duplication. Polo-like kinase 4 (PLK4) is a master regulator of biogenesis, initiating the recruitment of structural components. STIL and SAS-6 form a cartwheel-like structure at the proximal end, establishing the ninefold symmetry characteristic of centrioles. Surrounding pericentriolar material (PCM) acts as a hub for microtubule nucleation by concentrating γ-tubulin ring complexes, ensuring efficient microtubule organization.

Centrioles exhibit structural plasticity, adapting to different cellular contexts while maintaining core architecture. In multiciliated cells, they function as basal bodies, anchoring motile cilia. Proteins such as CEP164 and ODF2 are enriched in basal bodies, distinguishing them from centrosomal centrioles. Post-translational modifications, including acetylation and polyglutamylation of tubulin subunits, influence stability and function, highlighting intricate regulatory mechanisms.

Role In Cell Division

Centrioles orchestrate cell division by organizing the mitotic spindle and ensuring accurate chromosome segregation. As cells transition to mitosis, centrioles duplicate and migrate to opposite poles, forming centrosomes that nucleate spindle fibers. These fibers attach to kinetochores on chromosomes, facilitating alignment along the metaphase plate. Precise regulation prevents errors in chromosome distribution, which can lead to aneuploidy and tumorigenesis.

Beyond spindle formation, centrioles regulate the timing and symmetry of division. Their positioning influences mitotic spindle orientation, dictating the plane of cytokinesis. In asymmetrically dividing cells, such as stem cells, centriole-associated proteins like LGN and NuMA ensure one daughter cell retains stem-like properties while the other differentiates. This regulation is crucial in neurogenesis, where disruptions in centriole positioning have been linked to neurodevelopmental disorders.

Checkpoint mechanisms monitor centriole duplication and segregation to prevent mitotic errors. The anaphase-promoting complex (APC/C) regulates the degradation of key proteins, ensuring centrioles do not overduplicate. Kinases like Aurora A and PLK1 modulate centriole maturation, promoting pericentriolar material recruitment for robust spindle formation. Dysregulation of these pathways can lead to centrosome amplification, a hallmark of many cancers. Cells with extra centrioles often experience multipolar divisions, resulting in chromosomal instability and tumor progression.

Mechanisms Of Duplication

Centriole duplication is a tightly controlled process ensuring each daughter cell inherits a single centrosome with two centrioles. This duplication occurs once per cell cycle, initiating at the G1-to-S phase transition. PLK4, a master regulator, accumulates at the proximal end of the existing centriole, recruiting STIL and SAS-6 to form a cartwheel-like scaffold that establishes ninefold symmetry. Aberrant PLK4 levels can lead to centriole overduplication, frequently observed in cancer cells.

As the cartwheel stabilizes, additional proteins reinforce elongation and maturation. CEP135 and CPAP facilitate microtubule triplet extension, maintaining cylindrical architecture. Tubulin polymerization is tightly regulated, as premature elongation can impair function. Simultaneously, PCM components coalesce around the duplicating centriole, preparing it for microtubule organization. These molecular interactions are influenced by phosphorylation events, with kinases such as CDK2 and PLK1 modulating stability and timing. Disruptions in these phosphorylation cascades can produce defective centrioles, impairing centrosome assembly.

Centriole duplication is self-limiting, preventing uncontrolled accumulation. This restriction is maintained by regulatory pathways that suppress excessive PLK4 activity once a single daughter centriole has formed. The ubiquitin-proteasome system plays a key role, targeting PLK4 for degradation. SCF ubiquitin ligase complexes, particularly those containing βTrCP, mediate PLK4 turnover, ensuring duplication occurs only once per cycle. Mutations disrupting this degradation pathway can cause centriole amplification, leading to multipolar spindle formation and genomic instability.

Control Of Ciliogenesis

Ciliogenesis requires centrioles to transition into basal bodies, anchoring and organizing cilia formation. This transformation depends on precise molecular signaling to ensure proper assembly and function. The conversion begins with the recruitment of distal and transition zone proteins such as CEP164, which facilitates centriole docking to the plasma membrane. This step is essential for establishing a functional ciliary compartment, as defects can lead to ciliopathies characterized by impaired signaling and motility.

Once the basal body is established, intraflagellar transport (IFT) machinery elongates the ciliary axoneme. IFT complexes, composed of motor proteins such as kinesin-2 and dynein, shuttle structural components along the growing cilium, delivering tubulin subunits and signaling molecules. Proteins such as BBSome regulate cargo selection and transport efficiency. Disruptions in IFT dynamics have been implicated in disorders like Bardet-Biedl syndrome, where defective ciliary transport leads to multisystem dysfunction.

Links To Cellular Disorders

Defects in centriole structure, duplication, and function contribute to various cellular disorders, often manifesting as developmental abnormalities or proliferative diseases. Given their role in organizing microtubules and ensuring proper division, disruptions in centriole homeostasis can lead to chromosomal instability and tissue disorganization.

One well-documented condition linked to centriole dysfunction is microcephaly, a neurodevelopmental disorder characterized by reduced brain size. Mutations in genes such as CEP152 and STIL, which regulate duplication, disrupt neural progenitor cell division. These defects result in premature cell cycle exit and depletion of the progenitor pool, leading to structural abnormalities in the developing brain.

Centriole dysregulation is also frequently observed in cancer, where centrosome amplification contributes to tumor progression. Cells with extra centrioles undergo aberrant mitotic divisions, generating aneuploid daughter cells. This chromosomal instability drives malignancy in cancers such as breast, ovarian, and colorectal carcinomas. Overexpression of PLK4 correlates with aggressive tumor phenotypes and poor clinical outcomes. Targeting centriole amplification is an emerging therapeutic strategy, with PLK4 inhibitors being explored for their potential to selectively eliminate cancer cells exhibiting centrosome abnormalities.