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XB-ART-58892
Proc Natl Acad Sci U S A January 1, 2022; 119 (17): e2201008119.
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Lysosomes are required for early dorsal signaling in the Xenopus embryo.

Tejeda-Muñoz N , De Robertis EM .


Abstract
Lysosomes are the digestive center of the cell and play important roles in human diseases, including cancer. Previous work has suggested that late endosomes, also known as multivesicular bodies (MVBs), and lysosomes are essential for canonical Wnt pathway signaling. Sequestration of Glycogen Synthase 3 (GSK3) and of β‐catenin destruction complex components in MVBs is required for sustained canonical Wnt signaling. Little is known about the role of lysosomes during early development. In the Xenopus egg, a Wnt-like cytoplasmic determinant signal initiates formation of the body axis following a cortical rotation triggered by sperm entry. Here we report that cathepsin D was activated in lysosomes specifically on the dorsal marginal zone of the embryo at the 64-cell stage, long before zygotic transcription starts. Expansion of the MVB compartment with low-dose hydroxychloroquine (HCQ) greatly potentiated the dorsalizing effects of the Wnt agonist lithium chloride (LiCl) in embryos, and this effect required macropinocytosis. Formation of the dorsal axis required lysosomes, as indicated by brief treatments with the vacuolar ATPase (V-ATPase) inhibitors Bafilomycin A1 or Concanamycin A at the 32-cell stage. Inhibiting the MVB-forming machinery with a dominant-negative point mutation in Vacuolar Protein Sorting 4 (Vps4-EQ) interfered with the endogenous dorsal axis. The Wnt-like activity of the dorsal cytoplasmic determinant Huluwa (Hwa), and that of microinjected xWnt8 messenger RNA, also required lysosome acidification and the MVB-forming machinery. We conclude that lysosome function is required for early dorsal axis development in Xenopus. The results highlight the intertwining between membrane trafficking, lysosomes, and vertebrate axis formation.

PubMed ID: 35446621
Article link: Proc Natl Acad Sci U S A
Grant support: [+]

Species referenced: Xenopus laevis
Genes referenced: atn1 axin1 baf-l banf1 cd63 chrd.1 dvl2 egr2 fn1 gsk3a gsk3b hwa lrp6 mrc1 nodal3.1 pak1 rax sia1 sox2 szl ventx1.2 wnt3a wnt8a
GO keywords: lysosome [+]
Antibodies: Pak1 Ab2
Morpholinos: atn1 MO1

Disease Ontology terms: cancer

Article Images: [+] show captions
References [+] :
Albrecht, Cell Biology of Canonical Wnt Signaling. 2022, Pubmed