The Role of SEL-5/AAK1 Kinase in Regulating Cell Migration and Excretory Canal Outgrowth in Caenorhabditis elegans

Core Concepts

SEL-5, the C. elegans orthologue of mammalian AP2-associated kinase AAK1, acts together with the retromer complex to positively regulate Wnt signaling during cell migration and excretory canal outgrowth, independently of its kinase activity.

Abstract

The study investigates the role of the SEL-5 kinase, the C. elegans orthologue of mammalian AAK1, in regulating cell migration and excretory canal outgrowth. The key findings are:

SEL-5 acts together with the retromer complex as a positive regulator of EGL-20/Wnt signaling during the migration of QL neuroblast daughter cells. This role of SEL-5 is independent of its kinase activity and the phosphorylation of the AP2 subunit DPY-23.

SEL-5, in cooperation with the retromer complex, is also required for the active phase of excretory canal cell outgrowth, again independently of its kinase activity.

The Wnt proteins CWN-1 and CWN-2, together with the Frizzled receptor CFZ-2, positively regulate excretory canal outgrowth, while LIN-44/Wnt and LIN-17/Frizzled generate a stop signal inhibiting its extension.

The initial growth of the excretory canals is not affected in lin-17, lin-44 and mig-14 mutants, suggesting these mutants miss a signal determining the final position of the canal in later larval stages.

The role of SEL-5 in regulating excretory canal outgrowth is mediated through both cell-autonomous and non-autonomous mechanisms.

Stats

The level of DPY-23 phosphorylation at position T160 is reduced in sel-5 mutant animals compared to wild type.
The number of EGL-20 particles is substantially reduced in sel-5 vps-29 mutants compared to control animals.
The posterior excretory canals are shorter already at the time of hatching in sel-5 vps-29 mutants compared to wild type.

Quotes

"SEL-5 acts together with the retromer complex as a positive regulator of EGL-20/Wnt signalling during the migration of QL neuroblast descendants."
"SEL-5 together with the retromer complex is also required during the active phase of excretory canal cell outgrowth, again independently of its kinase activity."
"Wnt proteins CWN-1 and CWN-2 together with Frizzled receptor CFZ-2 positively regulate excretory canal outgrowth, while LIN-44/Wnt and LIN-17/Frizzled together generate a stop signal inhibiting its extension."

Key Insights Distilled From

Caenorhabditis elegans SEL-5/AAK1 regulates cell migration and cell outgrowth independently of its kinase activity

by Knop,F., Zou... at www.biorxiv.org 03-30-2023

https://www.biorxiv.org/content/10.1101/2023.03.29.534638v2

Deeper Inquiries

How might the non-autonomous role of SEL-5 in regulating excretory canal outgrowth be mediated through the hypodermis?

The non-autonomous role of SEL-5 in regulating excretory canal outgrowth through the hypodermis could be mediated by the secretion of signaling molecules or factors from the hypodermis that influence the development and growth of the excretory canal. The hypodermis in C. elegans plays a crucial role in cuticle synthesis, molting, and body shape determination. It is also involved in the secretion of extracellular matrix components and signaling molecules that can affect neighboring tissues and cells. SEL-5 expression in the hypodermis may modulate the secretion of factors that impact the guidance cues or signaling pathways necessary for proper excretory canal outgrowth. This could involve the release of Wnt ligands, growth factors, or other signaling molecules that influence the behavior and growth of the excretory canal cells.

What other endocytic cargoes or pathways might be affected by the loss of SEL-5 that could contribute to the observed phenotypes?

Apart from MIG-14/Wls, other endocytic cargoes or pathways that might be affected by the loss of SEL-5 and contribute to the observed phenotypes could include receptors or signaling components involved in Wnt signaling, Notch signaling, or other developmental pathways. For example, SEL-5 could regulate the endocytosis of Frizzled receptors, LRP6, or other components of the Wnt signaling pathway, impacting the reception and transduction of Wnt signals. Additionally, SEL-5 may influence the endocytosis of Notch receptors or ligands, affecting Notch signaling pathways that are crucial for cell fate determination and development. Disruption of endocytic pathways for these key signaling components could lead to aberrant cell migration, growth, or differentiation, contributing to the observed phenotypes in the context of SEL-5 loss.

What are the potential connections between the Wnt-dependent regulation of cell migration and excretory canal outgrowth, and how might these processes be integrated during development?

The potential connections between Wnt-dependent regulation of cell migration and excretory canal outgrowth lie in the shared signaling pathways and molecular mechanisms that govern both processes. Wnt signaling is a critical regulator of cell migration, polarity, and tissue morphogenesis during development. In the context of C. elegans, Wnt ligands and their receptors play essential roles in guiding cell migration along the A-P body axis and in establishing proper tissue architecture. The same Wnt signaling components that control neuronal migration, such as LIN-44/Wnt and LIN-17/Frizzled, are also involved in determining the length and growth of the excretory canal.
During development, the integration of Wnt signaling pathways for cell migration and excretory canal outgrowth involves the coordinated action of multiple Wnt ligands, receptors, and downstream effectors. The guidance cues provided by Wnt ligands help direct the migration of cells like the QL neuroblast descendants and influence the extension of the excretory canal. The interplay between attractive and repulsive Wnt signals, as well as the modulation of Wnt receptor activity, determines the direction and extent of cell migration and canal outgrowth. By sharing common Wnt signaling components and regulatory mechanisms, the processes of cell migration and excretory canal outgrowth can be tightly coordinated and integrated to ensure proper development and tissue patterning in C. elegans.