The LGN protein promotes planar proliferative divisions in the neocortex but apicobasal asymmetric terminal divisions in the retina

Abstract

Cell division orientation is crucial to control segregation of polarized fate determinants in the daughter cells to produce symmetric or asymmetric fate outcomes. Most studies in vertebrates have focused on the role of mitotic spindle orientation in proliferative asymmetric divisions and it remains unclear whether altering spindle orientation is required for the production of asymmetric fates in differentiative terminal divisions. Here, we show that the GoLoco motif protein LGN, which interacts with Gαi to control apicobasal division orientation in Drosophila neuroblasts, is excluded from the apical domain of retinal progenitors undergoing planar divisions, but not in those undergoing apicobasal divisions. Inactivation of LGN reduces the number of apicobasal divisions in mouse retinal progenitors, whereas it conversely increases these divisions in cortical progenitors. Although LGN inactivation increases the number of progenitors outside the ventricular zone in the developing neocortex, it has no effect on the position or number of progenitors in the retina. Retinal progenitor cell lineage analysis in LGN mutant mice, however, shows an increase in symmetric terminal divisions producing two photoreceptors, at the expense of asymmetric terminal divisions producing a photoreceptor and a bipolar or amacrine cell. Similarly, inactivating Gαi decreases asymmetric terminal divisions, suggesting that LGN function with Gαi to control division orientation in retinal progenitors. Together, these results show a context-dependent function for LGN and indicate that apicobasal divisions are not involved in proliferative asymmetric divisions in the mouse retina, but are instead essential to generate binary fates at terminal divisions.

LGN plays distinct roles in oral epithelial stratification, filiform papilla morphogenesis and hair follicle development

“…However, in epidermis, we and others have shown that LGN forms an apical complex with Insc, Gαi3, NuMA, dynactin and Par3 and that LGN loss leads to loss of perpendicular divisions, impaired Notch signaling and lethal defects in epidermal barrier formation and differentiation (Lechler and Fuchs, 2005;Poulson and Lechler, 2010;Williams et al, 2011Williams et al, , 2014. Similar roles for LGN in promoting perpendicular/ asymmetric divisions have been reported in retina and mammary gland (Ballard et al, 2015;Chiu et al, 2016;Lacomme et al, 2016). The molecular mechanisms that regulate the differential subcellular localization of LGN in progenitors undergoing both symmetric and asymmetric cell divisions remain largely unknown.…”

Proteostasis is essential during cochlear development for neuron survival and hair cell polarity

“…There is growing evidence that LGN and other intrinsic polarity protein members can regulate cellular asymmetry in a range of mitotic and non‐mitotic cells, including endothelial cells , retinal progenitor cells or glutamatergic neurons . Thus, it will be interesting to investigate if compromised proteostasis also interferes with polarity in these structures.…”

Development and dynamics of cell polarity at a glance

“…Work on mouse skin shows that the polarity regulators aPKC and Par3, together with Insc and the vertebrate homolog of Pins, LGN (also known as GPSM3), set the balance for symmetric and asymmetric stem cell divisions (Lechler and Fuchs, 2005;Poulson and Lechler, 2010). Recent evidence from retinal progenitors suggests similar mechanisms of polarity-and LGN-assisted asymmetric divisions during eye development (Lacomme et al, 2016).…”