Precise temporal control of neuroblast migration through combined regulation and feedback of a Wnt receptor

Abstract

Many developmental processes depend on precise temporal control of gene expression. We have previously established a theoretical framework for regulatory strategies that can govern such high temporal precision, but experimental validation of these predictions was still lacking. Here, we use the time-dependent expression of a Wnt receptor that controls neuroblast migration in C. elegans as a tractable system to study a robust, cell-intrinsic timing mechanism in vivo. Single molecule mRNA quantification showed that the expression of the receptor increases non-linearly, a dynamic that is predicted to enhance timing precision over an unregulated, linear increase in timekeeper abundance. We show that this upregulation depends on transcriptional activation, providing in vivo evidence for a model in which the timing of receptor expression is regulated through an accumulating activator that triggers expression when a specific threshold is reached. This timing mechanism acts across a cell division that occurs in the neuroblast lineage, and is influenced by the asymmetry of the division. Finally, we show that positive feedback of receptor expression through the canonical Wnt pathway enhances temporal precision. We conclude that robust cell-intrinsic timing can be achieved by combining regulation and feedback of the timekeeper gene.

MAB-5/Hox regulates the Q neuroblast transcriptome, includingcwn-1/Wnt,to mediate posterior migration inCaenorhabditis elegans

“…2011). Furthermore, evidence of a negative feedback loop between MIG-1 and the Wnt signaling pathway has been previously shown (SCHILD et al . 2023), although the negative transcriptional regulation of MIG-1 was proposed to be MAB-5 independent (JI et al .…”

“…shown (SCHILD et al 2023), although the negative transcriptional regulation of MIG-1 was proposed to be MAB-5 independent (JI et al 2013). However, based on our data, it is possible that MAB-5 is directly involved in regulating MIG-1 transcription via a negative feedback loop.…”

“…In QR, anterior migration of the QR descendants is dependent on non-canonical, β-catenin-independent signaling pathways, which do not result in the expression and activation of MAB-5 (ZINOVYEVA AND FORRESTER 2005; MENTINK et al . 2014; SCHILD et al . 2023).…”

“…In QL, EGL-20/Wnt is required to activate MAB-5 expression. In QR, anterior migration of the QR descendants is dependent on non-canonical, β-cateninindependent signaling pathways, which do not result in the expression and activation of MAB-5 (ZINOVYEVA AND FORRESTER 2005;MENTINK et al 2014;SCHILD et al 2023). Furthermore, MAB-5 participates in feedback regulation to adjust Wnt-signaling responses (JI et al 2013).…”