Early precision of radial patterning of the mouse cochlea is achieved by a linear BMP signaling gradient and is further refined by SOX2 DOI Creative Commons
Matthew J. Thompson, Vidhya Munnamalai, David M. Umulis

et al.

bioRxiv (Cold Spring Harbor Laboratory), Journal Year: 2022, Volume and Issue: unknown

Published: Aug. 30, 2022

Positional information encoded in signaling molecules is essential for early patterning the prosensory domain of developing cochlea. The cochlea contains an exquisite repeating pattern sensory hair cells and supporting cells. This requires precision morphogen signals that set initial radial compartment boundaries, but this has not been investigated. To measure gradient formation morphogenetic cochlea, we developed a quantitative image analysis procedure measuring SOX2 pSMAD1/5/9 profiles mouse embryos at embryonic day (E)12.5, E13.5, E14.5. Intriguingly, found profile forms linear medial ∼75% PSD during E12.5 E13.5. surprising activity readout diffusive BMP4 ligand secreted from tightly constrained lateral region 1,2 since morphogens typically form exponential or power-law shapes. meaningful interpretation because while offer theoretically highest content distributed patterning, yet observed. In addition to information-optimized profile, stable timeframe, accompanying shifts dynamically. Third, see through joint decoding maps there high-fidelity mapping between position regions soon become Kölliker’s organ Corti, where patterns are more intricate than regions. Mapping ambiguous precursory outer sulcus, cell fates uniform. Altogether, research provides new insights into cues domain. Summary Paragraph Corti precisely patterned group responsible transforming sound energy our perception hearing. Morphogenetic encoding positional crucial stages along cochlea’s axis. transcription factors together serve as integrative E14.5 However, role spatiotemporal these unknown. Here show establish spanning reference frame further refines precision. We signal retains its shape across least 24 h development dynamically shifts. global point information, improves local with steep slopes. Furthermore, unexpected, suggesting unidentified mechanisms BMP regulation unique system. A version source-sink model creating modified original formulation 3 explored system, enabling tight fit data. expect methods results shown here be starting increased cochlear measurements enable modeling experimental inquiry. combination mechanistic explanation how form, interpretations their properties, revealing why they certain way, potent basis biological discovery may even applied design synthetic systems.

Language: Английский

The role of Evi/Wntless in exporting Wnt proteins DOI Creative Commons
Lucie Wolf, Michael Boutros

Development, Journal Year: 2023, Volume and Issue: 150(3)

Published: Feb. 10, 2023

ABSTRACT Intercellular communication by Wnt proteins governs many essential processes during development, tissue homeostasis and disease in all metazoans. Many context-dependent effects are initiated the Wnt-producing cells depend on export of lipidated proteins. Although much focus has been understanding intracellular signal transduction, cellular machinery responsible for secretion became better understood only recently. After lipid modification acyl-transferase Porcupine, bind their dedicated cargo protein Evi/Wntless transport secretion. Porcupine conserved transmembrane proteins, 3D structures were recently determined. In this Review, we summarise studies structural data highlighting how Wnts transported from ER to plasma membrane, role SNX3-retromer recycling its receptor Evi/Wntless. We also describe regulation through a post-translational mechanism review importance organ development cancer, as future biomarker.

Language: Английский

Citations

9
Wnt7b acts in concert with Wnt5a to regulate tissue elongation and planar cell polarity via noncanonical Wnt signaling DOI Creative Commons

Nicholas Xie,

André Landin Malt,

Aray Adylkhan

et al.

Proceedings of the National Academy of Sciences, Journal Year: 2024, Volume and Issue: 121(35)

Published: Aug. 22, 2024

Intercellular signaling mediated by evolutionarily conserved planar cell polarity (PCP) proteins aligns along the tissue plane and drives polarized behaviors during morphogenesis. Accumulating evidence indicates that vertebrate PCP pathway is regulated noncanonical, β-catenin-independent Wnt signaling; however, components mechanisms are incompletely understood. In mouse hearing organ, both noncanonical (ncWnt) required in developing auditory sensory epithelium to control cochlear duct elongation of resident hair cells (HCs), including shape orientation stereociliary bundle essential for sound detection. We have recently discovered a Wnt/G-protein/PI3K coordinates HC intercellular signaling. Here, we identify Wnt7b as ncWnt ligand acting concert with Wnt5a promote diverse developmental processes. cochlea, redundantly coiling elongation, polarity, asymmetric localization core Fzd6 Dvl2. Mechanistically, Wnt5a/Wnt7b-mediated promotes membrane recruitment Daple, nonreceptor guanine nucleotide exchange factor Gαi, activates PI3K/AKT ERK signaling, which localization. Thus, pathways distinct mutant phenotypes components, suggesting they act separate, parallel nonoverlapping functions NcWnt reinforces regulating trafficking PCP-specific Frizzled receptors.

Language: Английский

Citations

3
Early radial positional information in the cochlea is optimized by a precise linear BMP gradient and enhanced by SOX2 DOI Creative Commons
Matthew J. Thompson, Caryl A. Young, Vidhya Munnamalai

et al.

Scientific Reports, Journal Year: 2023, Volume and Issue: 13(1)

Published: May 26, 2023

Abstract Positional information encoded in signaling molecules is essential for early patterning the prosensory domain of developing cochlea. The sensory epithelium, organ Corti, contains an exquisite repeating pattern hair cells and supporting cells. This requires precision morphogen signals that set initial radial compartment boundaries, but this has not been investigated. To measure gradient formation morphogenetic cochlea, we developed a quantitative image analysis procedure measuring SOX2 pSMAD1/5/9 profiles mouse embryos at embryonic day (E)12.5, E13.5, E14.5. Intriguingly, found profile forms linear up to medial ~ 75% PSD from peak lateral edge during E12.5 E13.5. surprising activity readout diffusive BMP4 ligand secreted tightly constrained region since morphogens typically form exponential or power-law shapes. meaningful interpretation because while offer theoretically highest content distributed patterning, yet observed. Furthermore, unique cochlear epithelium as surrounding mesenchyme. In addition information-optimized profile, stable timeframe, accompanying shifts dynamically. Last, through joint decoding maps SOX2, see there high-fidelity mapping between position regions will become Kölliker’s Corti. Mapping ambiguous precursory outer sulcus. Altogether, research provides new insights into cues cochlea domain.

Language: Английский

Citations

5
A cochlear progenitor pool influences patterning of the mammalian sensory epithelium via MYBL2 DOI Creative Commons
Caryl A. Young, Emily K. Burt, Vidhya Munnamalai

et al.

Development, Journal Year: 2024, Volume and Issue: 151(17)

Published: Sept. 1, 2024

ABSTRACT During embryonic development, Wnt signaling influences both proliferation and sensory formation in the cochlea. How this dual nature of is coordinated unknown. In study, we define a novel role for Wnt-regulated gene, Mybl2, which was already known to be important proliferation, determining size patterning epithelium murine Using quantitative spatial analysis approach analyzing Mybl2 loss-of-function, show that promoted inner sulcus domain but limited by influencing their adjoining boundary position via Jag1 regulation during development. loss-of-function simultaneously decreased increased domain, resulting wider with ectopic hair cell late stages. These data suggest progenitor cells determine pattern MYBL2.

Language: Английский

Citations

0
Sensory progenitors influence patterning of the mammalian auditory sensory epithelium DOI Open Access
Caryl A. Young, Emily K. Burt, Vidhya Munnamalai

et al.

bioRxiv (Cold Spring Harbor Laboratory), Journal Year: 2023, Volume and Issue: unknown

Published: Nov. 13, 2023

Abstract During embryonic development Wnt signaling has been shown to influence proliferation and sensory formation in the cochlea. How dual nature of is coordinated unknown. In this study, we define a novel role for regulated gene, Mybl2, which was already known be important proliferation, influencing patterning determining size epithelium murine Using quantitative spatial analysis approach analyzing Mybl2 loss-of-function cochleas, show that simultaneously specifies progenitor niche domain, influences positioning medial domain boundary via Jag1 regulation during mid-gestational stages. conditional knockout resulted decrease within niche. late stages, produced wider across radial axis with an increase ectopic inner hair cell formation. These data suggest -positive progenitors play epithelium. Summary Statement Wnt-regulated gene encoding transcription factor expressed cochlear between mid-cochlear developmental thereby impacting

Language: Английский

Citations

0
Early precision of radial patterning of the mouse cochlea is achieved by a linear BMP signaling gradient and is further refined by SOX2 DOI Creative Commons
Matthew J. Thompson, Vidhya Munnamalai, David M. Umulis

et al.

bioRxiv (Cold Spring Harbor Laboratory), Journal Year: 2022, Volume and Issue: unknown

Published: Aug. 30, 2022

Positional information encoded in signaling molecules is essential for early patterning the prosensory domain of developing cochlea. The cochlea contains an exquisite repeating pattern sensory hair cells and supporting cells. This requires precision morphogen signals that set initial radial compartment boundaries, but this has not been investigated. To measure gradient formation morphogenetic cochlea, we developed a quantitative image analysis procedure measuring SOX2 pSMAD1/5/9 profiles mouse embryos at embryonic day (E)12.5, E13.5, E14.5. Intriguingly, found profile forms linear medial ∼75% PSD during E12.5 E13.5. surprising activity readout diffusive BMP4 ligand secreted from tightly constrained lateral region 1,2 since morphogens typically form exponential or power-law shapes. meaningful interpretation because while offer theoretically highest content distributed patterning, yet observed. In addition to information-optimized profile, stable timeframe, accompanying shifts dynamically. Third, see through joint decoding maps there high-fidelity mapping between position regions soon become Kölliker’s organ Corti, where patterns are more intricate than regions. Mapping ambiguous precursory outer sulcus, cell fates uniform. Altogether, research provides new insights into cues domain. Summary Paragraph Corti precisely patterned group responsible transforming sound energy our perception hearing. Morphogenetic encoding positional crucial stages along cochlea’s axis. transcription factors together serve as integrative E14.5 However, role spatiotemporal these unknown. Here show establish spanning reference frame further refines precision. We signal retains its shape across least 24 h development dynamically shifts. global point information, improves local with steep slopes. Furthermore, unexpected, suggesting unidentified mechanisms BMP regulation unique system. A version source-sink model creating modified original formulation 3 explored system, enabling tight fit data. expect methods results shown here be starting increased cochlear measurements enable modeling experimental inquiry. combination mechanistic explanation how form, interpretations their properties, revealing why they certain way, potent basis biological discovery may even applied design synthetic systems.

Language: Английский

Citations

0