Mutations in centrosome genes deplete neural progenitor cells (NPCs) during brain development, causing microcephaly. While NPC attrition is linked to TP53-mediated cell death in several microcephaly models, how TP53 is activated remains unclear. In cultured cells, mitotic delays resulting from centrosome loss prevent the growth of unfit daughter cells by activating a pathway involving 53BP1, USP28, and TP53, termed the mitotic surveillance pathway. Whether this pathway is active in the developing brain is unknown. Here, we show that the depletion of centrosome proteins in NPCs prolongs mitosis and increases TP53-mediated apoptosis. Cell death after a delayed mitosis was rescued by inactivation of the mitotic surveillance pathway. Moreover, 53BP1 or USP28 deletion restored NPC proliferation and brain size without correcting the upstream centrosome defects or extended mitosis. By contrast, microcephaly caused by the loss of the non-centrosomal protein SMC5 is also TP53-dependent but is not rescued by loss of 53BP1 or USP28. Thus, we propose that mutations in centrosome genes cause microcephaly by delaying mitosis and pathologically activating the mitotic surveillance pathway in the developing brain.

Centrosomes are microtubule-organizing centers comprised of a pair of centrioles and the surrounding pericentriolar material. Abnormalities in centriole number are associated with cell division errors and can contribute to diseases such as cancer. Centriole duplication is limited to once per cell cycle and is controlled by the dosage-sensitive Polo-like kinase 4 (PLK4). Here, we show that PLK4 abundance is translationally controlled through conserved upstream open reading frames (uORFs) in the 5′ UTR of the mRNA. Plk4 uORFs suppress Plk4 translation and prevent excess protein synthesis. Mice with homozygous knockout of Plk4 uORFs (Plk4Δu/Δu) are viable but display dramatically reduced fertility because of a significant depletion of primordial germ cells (PGCs). The remaining PGCs in Plk4Δu/Δu mice contain extra centrioles and display evidence of increased mitotic errors. PGCs undergo hypertranscription and have substantially more Plk4 mRNA than somatic cells. Reducing Plk4 mRNA levels in mice lacking Plk4 uORFs restored PGC numbers and fully rescued fertility. Together, our data uncover a specific requirement for uORF-dependent control of PLK4 translation in counterbalancing the increased Plk4 transcription in PGCs. Thus, uORF-mediated translational suppression of PLK4 has a critical role in preventing centriole amplification and preserving the genomic integrity of future gametes.

11002 Background: Gender disparity is an important issue in medicine, as women occupy a minority of academic leadership positions despite increased representation in the physician workforce. One important aspect is the gender gap of speakers at academic meetings, which limits opportunities for career advancement and mentorship. This underrepresentation of women is largely anecdotal in oncology. We hypothesized that original research is less frequently presented by women at the annual ASCO meeting. We sought to examine presentation patterns from recently featured ASCO speakers, categorized by presentation type and gender. Methods: We conducted a retrospective, observational review of data from the 2018-2021 ASCO annual meetings. Mixed-gender coders extracted data from the ASCO Annual Meeting library and institutional public websites. Speaker-identified gender was unavailable; binary gender was determined by presenter name, pronouns, and video files. For original research, we collected data on last authors as well as these roles are also considered meritorious. Cochran–Mantel–Haenszel tests were used to investigate the association of gender and roles adjusted for each stratification variable individually. Common odds ratios (ORs) were estimated for each association. Breslow-Day Tests were used to test the homogeneity of these ORs among the different levels of each stratification variable. No adjustments for multiple testing were used. Results: We reviewed 4267 unique presentations, including those which highlighted original research (Poster Discussion, Oral Abstract, Clinical Science Symposium, Plenary) vs. education (Case-Based Panel, Education Sessions, Highlights of the Day). For original research, women were significantly more likely to have an ASCO-appointed role (discussant, speaker, or chair) than a first or last author role (48% vs. 32.7% of presentations, p < 0.0001), even after adjusting for conference year (OR 0.53, 95% CI: 0.45-0.61), session type (0.52, 0.45-0.61), degree (0.50, 0.43-0.58), academic rank (0.55, 0.47-0.64), and geographic region (0.58, 0.50-0.68). There was no difference between in-person and virtual conferences (p = 0.584). For education sessions, women comprised 46.1% (n = 626), nearly half, of these speaking roles (all ASCO-appointed) compared with men. 38% of the data was independently re-reviewed to confirm accuracy; 96.4% concordance was observed in presenter gender. Conclusions: Women are less likely to present highlighted original research and are more likely to have an appointed educational role at ASCO annual meetings. This likely reflects broader gender disparity within academia. Future analyses could be improved by examining speaker-identified gender. As high-profile original research can elevate careers, examining factors contributing to this observed disparity may reveal important approaches to address gender leadership gaps in oncology.