INVESTIGATING THE ROLE OF AN ENDOGENOUS RETROELEMENT AT THE MATERNAL-FETAL INTERFACE
W B SAUNDERS CO LTD. 2023: E41
View details for Web of Science ID 001069701600124
Disruption of the nectin-afadin complex recapitulates features of the human cleft lip/palate syndrome CLPED1
2020; 147 (21)
Cleft palate (CP), one of the most common congenital conditions, arises from failures in secondary palatogenesis during embryonic development. Several human genetic syndromes featuring CP and ectodermal dysplasia have been linked to mutations in genes regulating cell-cell adhesion, yet mouse models have largely failed to recapitulate these findings. Here, we use in utero lentiviral-mediated genetic approaches in mice to provide the first direct evidence that the nectin-afadin axis is essential for proper palate shelf elevation and fusion. Using this technique, we demonstrate that palatal epithelial conditional loss of afadin (Afdn) - an obligate nectin- and actin-binding protein - induces a high penetrance of CP, not observed when Afdn is targeted later using Krt14-Cre We implicate Nectin1 and Nectin4 as being crucially involved, as loss of either induces a low penetrance of mild palate closure defects, while loss of both causes severe CP with a frequency similar to Afdn loss. Finally, expression of the human disease mutant NECTIN1W185X causes CP with greater penetrance than Nectin1 loss, suggesting this alteration may drive CP via a dominant interfering mechanism.
View details for DOI 10.1242/dev.189241
View details for Web of Science ID 000590574000015
View details for PubMedID 32554531
View details for PubMedCentralID PMC7375477
Telophase correction refines division orientation in stratified epithelia
During organogenesis, precise control of spindle orientation balances proliferation and differentiation. In the developing murine epidermis, planar and perpendicular divisions yield symmetric and asymmetric fate outcomes, respectively. Classically, division axis specification involves centrosome migration and spindle rotation, events occurring early in mitosis. Here, we identify a novel orientation mechanism which corrects erroneous anaphase orientations during telophase. The directionality of reorientation correlates with the maintenance or loss of basal contact by the apical daughter. While the scaffolding protein LGN is known to determine initial spindle positioning, we show that LGN also functions during telophase to reorient oblique divisions toward perpendicular. The fidelity of telophase correction also relies on the tension-sensitive adherens junction proteins vinculin, α-E-catenin, and afadin. Failure of this corrective mechanism impacts tissue architecture, as persistent oblique divisions induce precocious, sustained differentiation. The division orientation plasticity provided by telophase correction may enable progenitors to adapt to local tissue needs.
View details for DOI 10.7554/eLife.49249
View details for Web of Science ID 000507301200001
View details for PubMedID 31833472
View details for PubMedCentralID PMC6959978