Differential compartmentalization of BMP4/NOGGIN requires NOGGIN trans-epithelial transport.
Bone Morphogenetic Protein 4
/ genetics
Carrier Proteins
/ genetics
Cell Compartmentation
/ genetics
Embryonic Development
/ genetics
Extracellular Space
/ genetics
Gene Expression Regulation, Developmental
/ genetics
Humans
Microfluidics
Morphogenesis
/ genetics
Signal Transduction
/ genetics
Transcytosis
/ genetics
BMP4
NOGGIN
SMAD signaling
embryonic stem cells
endocytosis
epiblast
human
morphogen
polarity
transcytosis
Journal
Developmental cell
ISSN: 1878-1551
Titre abrégé: Dev Cell
Pays: United States
ID NLM: 101120028
Informations de publication
Date de publication:
12 07 2021
12 07 2021
Historique:
received:
10
12
2020
revised:
01
04
2021
accepted:
06
05
2021
pubmed:
30
5
2021
medline:
21
10
2021
entrez:
29
5
2021
Statut:
ppublish
Résumé
Using self-organizing human models of gastrulation, we previously showed that (1) BMP4 initiates the cascade of events leading to gastrulation, (2) BMP4 signal reception is restricted to the basolateral domain, and (3) in a human-specific manner, BMP4 directly induces the expression of NOGGIN. Here, we report the surprising discovery that in human epiblasts, NOGGIN and BMP4 were secreted into opposite extracellular spaces. Interestingly, apically presented NOGGIN could inhibit basally delivered BMP4. Apically imposed microfluidic flow demonstrated that NOGGIN traveled in the apical extracellular space. Our co-localization analysis detailed the endocytotic route that trafficked NOGGIN from the apical space to the basolateral intercellular space where BMP4 receptors were located. This apical-basal transcytosis was indispensable for NOGGIN inhibition. Taken together, the segregation of activator/inhibitor into distinct extracellular spaces challenges classical views of morphogen movement. We propose that the transport of morphogen inhibitors regulates the spatial availability of morphogens during embryogenesis.
Identifiants
pubmed: 34051144
pii: S1534-5807(21)00403-2
doi: 10.1016/j.devcel.2021.05.003
pmc: PMC8604396
mid: NIHMS1702277
pii:
doi:
Substances chimiques
BMP4 protein, human
0
Bone Morphogenetic Protein 4
0
Carrier Proteins
0
noggin protein
148294-77-3
Types de publication
Journal Article
Research Support, N.I.H., Extramural
Research Support, U.S. Gov't, Non-P.H.S.
Langues
eng
Sous-ensembles de citation
IM
Pagination
1930-1944.e5Subventions
Organisme : NIGMS NIH HHS
ID : R01 GM101653
Pays : United States
Organisme : NICHD NIH HHS
ID : R01 HD080699
Pays : United States
Informations de copyright
Copyright © 2021 Elsevier Inc. All rights reserved.
Déclaration de conflit d'intérêts
Declaration of interests F.E. is the chief scientific officer of Rumi Scientific. E.D.S. and A.H.B. are founders and members of the scientific advisory board of Rumi Scientific.
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