Annexin A1 is a polarity cue that directs planar mitotic spindle orientation during mammalian epithelial morphogenesis

Oriented cell divisions are critical for the formation and maintenance of structured epithelia. Proper mitotic spindle orientation relies on polarised anchoring of force generators to the cell cortex by the evolutionarily conserved Gαi-LGN-NuMA complex. However, the polarity cues that control cortical patterning of this ternary complex remain largely unknown in mammalian epithelia. Here we identify the membrane-associated protein Annexin A1 (ANXA1) as a novel interactor of LGN in mammary epithelial cells. ANXA1 acts independently of Gαi to instruct the accumulation of LGN and NuMA at the lateral cortex to ensure cortical anchoring of Dynein-Dynactin and astral microtubules and thereby planar alignment of the mitotic spindle. Loss of ANXA1 randomises mitotic spindle orientation, which in turn disrupts epithelial architecture and lumen formation in three-dimensional (3D) primary mammary organoids. Our findings establish ANXA1 as an upstream cortical cue that regulates LGN to direct planar cell divisions during mammalian epithelial morphogenesis.

Cross talk-dependent cortical patterning of Rho GTPases during cell repair

Rho GTPases such as Rho, Rac and Cdc42 are important regulators of the cortical cytoskeleton in processes including cell division, locomotion and repair. In these processes, Rho GTPases assume characteristic patterns wherein the active GTPases occupy mutually exclusive “zones” in the cell cortex. During cell wound repair, for example, a Rho zone encircles the wound edge and is in turn encircled by a Cdc42 zone. Here we evaluated the contributions of crosstalk between Rho and Cdc42 to the patterning of their respective zones in wounded Xenopus oocytes using experimental manipulations in combination with mathematical modeling. The results show that the position of the Cdc42 zone relative the Rho zone and relative to the wound edge is controlled by the level of Rho activity. In contrast, the outer boundary of the Rho zone is limited by the level of Cdc42 activity. Models based on positive feedback within zones and negative feedback from Rho to the GEF-GAP Abr to Cdc42 capture some, but not all, of the observed behaviors. We conclude that GTPase zone positioning is controlled at the level of Rho activity and we speculate that the Cdc42 zone or something associated with it limits the spread of Rho activity. [Media: see text] [Media: see text] [Media: see text] [Media: see text] [Media: see text] [Media: see text] [Media: see text] [Media: see text] [Media: see text] [Media: see text]

The Ran pathway uniquely regulates cytokinesis in cells with different fates in the early C. elegans embryo

ABSTRACTCytokinesis occurs at the end of mitosis and occurs due to the ingression of a contractile ring that cleaves the daughter cells. This process is tightly controlled to prevent cell fate changes or aneuploidy, and the core machinery is highly conserved among metazoans. Multiple mechanisms regulate cytokinesis, but their requirement in different cell types is not known. Here, we show that differently fated AB and P1 cells in the early C. elegans embryo have unique cytokinesis kinetics supported by distinct levels and cortical patterning of myosin. Through perturbation of polarity regulators and the generation of stable tetraploid strains, we demonstrate that these differences depend on both cell fate and size. Additionally, these parameters could influence the Ran pathway, which coordinates the contractile ring with chromatin position, and controls cytokinesis differently in AB and P1 cells. Our findings demonstrate the need to consider multiple parameters when modeling ring kinetics.

Atypical genomic patterning of the cerebral cortex in autism with poor early language outcome

Cortical regional identities develop through anterior-posterior (A-P) and dorsal-ventral (D-V) prenatal genomic patterning gradients. Here we find that A-P and D-V genomic patterning of cortical surface area (SA) and thickness (CT) is intact in typically developing and autistic toddlers with good language outcome, but is absent in autistic toddlers with poor early language outcome. Genes driving this effect are prominent in midgestational A-P and D-V gene expression gradients and prenatal cell types driving SA and CT variation (e.g., progenitor cells versus excitatory neurons). These genes are also important for vocal learning, human-specific evolution, and prenatal co-expression networks enriched for high-penetrance autism risk genes. Autism with poor early language outcome may be linked to atypical genomic cortical patterning starting in prenatal periods and which impacts later development of regional functional specialization and circuit formation.One Sentence SummaryGenomic patterning of the cortex is atypical in autistic toddlers with poor early language outcome.

Increased p53 signaling impairs neural differentiation causing HUWE1-promoted intellectual disabilities

SUMMARYEssential E3 ubiquitin ligase HUWE1 (HECT, UBA and WWE domain containing 1) regulates key factors, as p53. Mutations in HUWE1 have been associated with neurodevelopmental X-linked intellectual disabilities (XLIDs), however the pathomechanism at the onset of heterogenous XLIDs remains unknown. In this work, we identify p53 signaling as the process hyperactivated in lymphoblastoid cells from patients with HUWE1-promoted XLIDs. The hiPSCs-based modeling of the severe HUWE1-promoted XLID, the Juberg Marsidi syndrome (JMS), reviled majorly impaired neural differentiation, accompanied by increased p53 signaling. The impaired differentiation results in loss of cortical patterning and overall undergrowth of XLID JMS patient-specific cerebral organoids, thus closely recapitulating key symptoms, as microcephaly. Importantly, the neurodevelopmental potential of JMS hiPSCs is successfully rescued by restoring p53 signaling, upon reduction of p53 levels. In summary, our findings indicate that increased p53 signaling leads to impaired neural differentiation and is the common cause of neurodevelopmental HUWE1-promoted XLIDs.