Dynamic regulation and requirement for ribosomal RNA transcription during mammalian development.

Ribosomal RNA (rRNA) transcription by RNA polymerase I (Pol I) is a critical rate-limiting step in ribosome biogenesis, which is essential for cell survival. Despite its global function, disruptions in ribosome biogenesis cause tissue-specific birth defects called ribosomopathies, which frequently affect craniofacial development. Here, we describe a cellular and molecular mechanism underlying the susceptibility of craniofacial development to disruptions in Pol I transcription. We show that Pol I subunits are highly expressed in the neuroepithelium and neural crest cells (NCCs), which generate most of the craniofacial skeleton. High expression of Pol I subunits sustains elevated rRNA transcription in NCC progenitors, which supports their high tissue-specific levels of protein translation, but also makes NCCs particularly sensitive to rRNA synthesis defects. Consistent with this model, NCC-specific deletion of Pol I subunits Polr1a, Polr1c, and associated factor Tcof1 in mice cell-autonomously diminishes rRNA synthesis, which leads to p53 protein accumulation, resulting in NCC apoptosis and craniofacial anomalies. Furthermore, compound mutations in Pol I subunits and associated factors specifically exacerbate the craniofacial anomalies characteristic of the ribosomopathies Treacher Collins syndrome and Acrofacial Dysostosis-Cincinnati type. Mechanistically, we demonstrate that diminished rRNA synthesis causes an imbalance between rRNA and ribosomal proteins. This leads to increased binding of ribosomal proteins Rpl5 and Rpl11 to Mdm2 and concomitantly diminished binding between Mdm2 and p53. Altogether, our results demonstrate a dynamic spatiotemporal requirement for rRNA transcription during mammalian cranial NCC development and corresponding tissue-specific threshold sensitivities to disruptions in rRNA transcription in the pathogenesis of congenital craniofacial disorders.

Risk Factors for Hardware-Related Complications After Olecranon Fracture Fixation.

The aim of this study was to evaluate risk factors for symptomatic hardware and removal of hardware (ROH) after olecranon open reduction and internal fixation (ORIF) and to assess differences between olecranon locking plate and screws (P&S) or tension band (TB) wire cohorts. The medical records of 331 patients with olecranon fractures treated at two academic level I trauma centers with ORIF from 2012 to 2016 were reviewed. A total of 189 patients were included in the study. Complications, ROH, and subsequent surgery were assessed and compared between cohorts. There were 124 cases in the P&S cohort and 65 in the TB cohort. The overall reoperation rate was 31.2% (59 of 189). The overall incidence of ROH for all cases was 29.1% (55 of 189). Patients who required ROH or developed symptomatic hardware were significantly younger than those who did not (P&S, P<.003; TB, P<.004). Age and body mass index (BMI) were associated with ROH plus symptomatic hardware after P&S. Age (but not BMI) was associated with ROH/symptomatic hardware after TB. Measured hardware prominence was not associated with ROH or ROH plus symptomatic hardware for either the P&S or the TB cohort. Risk factors including patient age and BMI were found to be significantly associated with hardware-related complications. [Orthopedics. 2020;43(3):141-146.].