Ciliary transition zone activation of phosphorylated Tctex-1 controls ciliary resorption, S-phase entry and fate of neural progenitors

Abstract

Primary cilia are displayed during the G0/G1 phase of many cell types. Cilia are reabsorbed as cells prepare to re-enter the cell cycle, but the causal and molecular link between these two cellular events remains unclear. We show that phospho(T94)Tctex-1 is recruited to ciliary transition zones prior to S-phase entry and plays a pivotal role in both ciliary disassembly and cell cycle progression. Tctex-1’s role in S-phase entry, however, is dispensable in non-ciliated cells. Exogenously added phosphomimic Tctex-1 T94E accelerates cilium disassembly and S-phase entry. These results support a model in which the cilia act as a brake to prevent cell cycle progression. Mechanistic studies show the involvement of actin dynamics in Tctex-1 regulated cilium resorption. Phospho(T94)Tctex-1 is also selectively enriched at the ciliary transition zones of cortical neural progenitors, and plays a key role in controlling G1 length, cell cycle entry, and fate determination of these cells during corticogenesis.

CPAP promotes timely cilium disassembly to maintain neural progenitor pool

“…In vertebrate cells, an elongated cilium is associated with suppression of cell division via a delay in G1‐S transition (Jackson, 2011; Kim et al , 2011; Li et al , 2011). As Seckel cells have long cilia, we speculated that they would also have a delayed G1‐S transition.…”

“…It is known that the horizontal orientation of the cleavage plane of mitotic apical progenitors is essential for early symmetric expansion of NPCs (Yingling et al , 2008; Li et al , 2011). After sufficient NPCs expansion, neurogenesis then begins, which requires switching of the cleavage plane from horizontal to vertical (Rakic, 1995; Lancaster et al , 2013).…”

“…The cilium is the primary microtubule‐based organelle that is dynamically regulated, with assembly occurring during cell cycle exit, and disassembly coinciding with cell cycle re‐entry (Jackson, 2011; Kim et al , 2011; Paridaen et al , 2013; Guemez‐Gamboa et al , 2014). Thus, a delay or failure in cilium disassembly could act as a brake, retaining cells in G0/G1 and transiently preventing cell cycle progression (Jackson, 2011; Kim et al , 2011; Li et al , 2011). …”

“…By impairing stem cell division even mildly, the proportion of symmetric divisions is concomitantly reduced, depleting the progenitor pool and limiting the total number of neurons that can be generated (Thornton & Woods, 2009; Alcantara & O'Driscoll, 2014). On the other hand, altering the cell cycle length, in particular the G1 phase, contributes to switching of neural progenitors from proliferative to differentiating states (Calegari et al , 2005; Lange et al , 2009; Li et al , 2011). …”

“…However, since centrosomes template ciliogenesis, it is conceivable that altered ciliogenesis could underlie the pathophysiology of microcephaly. Recent studies have uncovered that the proper timing of cilium disassembly mediated by Nde‐1 and TcTex‐1 is critically regulated during cell cycle (Kim et al , 2011; Li et al , 2011; Maskey et al , 2015). Interestingly, mutations in Nde‐1 and microtubule and kinetochore components causing microcephaly and ciliary defects highlight a possible role for the cilium in regulating NPCs to control the number of neurons generated during brain development (Alkuraya et al , 2011; Hu et al , 2014; Waters et al , 2015).…”