A dual role of the C9ORF72/SMCR8-containing complex in autophagy initiation and autophagic flux.

Primary microcephaly is caused by mutations in genes encoding centrosomal proteins including WDR62 and KIF2A. However, mechanisms underlying human microcephaly remain elusive. By creating mutant mice and human cerebral organoids, here we found that WDR62 deletion resulted in a reduction in the size of mouse brains and organoids due to the disruption of neural progenitor cells (NPCs), including outer radial glia (oRG). WDR62 ablation led to retarded cilium disassembly, long cilium, and delayed cell cycle progression leading to decreased proliferation and premature differentiation of NPCs. Mechanistically, WDR62 interacts with and promotes CEP170’s localization to the basal body of primary cilium, where CEP170 recruits microtubule-depolymerizing factor KIF2A to disassemble cilium. WDR62 depletion reduced KIF2A’s basal body localization, and enhanced KIF2A expression partially rescued deficits in cilium length and NPC proliferation. Thus, modeling microcephaly with cerebral organoids and mice reveals a WDR62-CEP170-KIF2A pathway promoting cilium disassembly, disruption of which contributes to microcephaly.

No abstract

Neural progenitor cells (NPCs) have distinct proliferation capacities at different stages of brain development. Lin28 is an RNA-binding protein with two homologs in mice: Lin28a and Lin28b. Here we show that Lin28a/b are enriched in early NPCs and their expression declines during neural differentiation. Lin28a single-knockout mice show reduced NPC proliferation, enhanced cell cycle exit and a smaller brain, whereas mice lacking both Lin28a alleles and one Lin28b allele display similar but more severe phenotypes. Ectopic expression of Lin28a in mice results in increased NPC proliferation, NPC numbers and brain size. Mechanistically, Lin28a physically and functionally interacts with Imp1 (Igf2bp1) and regulates Igf2-mTOR signaling. The function of Lin28a/b in NPCs could be attributed, at least in part, to the regulation of their mRNA targets that encode Igf1r and Hmga2. Thus, Lin28a and Lin28b have overlapping functions in temporally regulating NPC proliferation during early brain development.

Background:The feasibility and practicality of preoperative rehabilitation (PR) programs remains quite controversial in the treatment of lung cancer (LC). This study explored whether a short-term high-intensity rehabilitation program could improve postoperative outcomes compared to those achieved with conventional inspiratory muscle training (IMT).Methods: A three-armed randomized controlled trial comparing the two training modalities and routine care was conducted in surgical LC patients. Patient groups received one of three treatment regimens: (I) high-intensity pulmonary rehabilitation (PR) that combined IMT with conventional resistance training (CRT) (combined PR group); (II) conventional PR (single IMT group); or (III) routine preoperative preparation (control group). The primary endpoint was a change in the occurrence of post-operative pulmonary complications (PPCs) that occurred within 30 days after surgery, while secondary endpoints included changes in length of hospital stay, quality of life (QoL) scores, 6-min walk distance (6-MWD) and peak expiratory flow (PEF).Results: A total of 90 enrolled patients were randomized into three groups with a computer-based 1:1:1 ratio. The intention-to-treat analysis of the study revealed that, compared with the Control Group, the Combined PR Group had a significant increase in Conclusions: This hospital-based short-term program of PR combining high-intensity IMT with CRT was significantly superior to the conventional IMT program, indicating that this approach would be a feasible strategy for treating LC patients, especially those waiting operations with surgery-related risk factors.