FGF20-Expressing, Wnt-Responsive Olfactory Epithelial Progenitors Regulate Underlying Turbinate Growth to Optimize Surface Area

Yang, Lu; Huh, Sung Ho; Ornitz, David M.

doi:10.1016/j.devcel.2018.07.010

Cited by 28 publications

(21 citation statements)

References 59 publications

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“…Here we provide evidence that FGF20 directly promotes the early DC precursor fate before DC cluster formation. Similarly, recent identification of an Fgf20-expressing olfactory epithelial stem cell niche revealed a Wnt-regulated FGF20 requirement for formation of the underlying mesenchymal condensations that form nasal turbinates (Yang et al, 2018). Taken together these data indicate that the progenitors in nascent hair follicle pre-Pc signal to underlying Fb at least in part through FGF20 to induce the early DC fate prior to cluster-forming migration, and unequivocally demonstrate that progenitor fate precedes establishment of its supportive niche.…”

Section: Discussionmentioning

confidence: 98%

Dermal Condensate Niche Fate Specification Occurs Prior to Formation and Is Placode Progenitor Dependent

et al. 2019

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SUMMARY Cell fate transitions are essential for specification of stem cells and their niches, but the precise timing and sequence of molecular events during embryonic development are largely unknown. Here, we identify with 3D/4D microscopy unclustered precursors of dermal condensates (DC), signaling niches for epithelial progenitors in hair placodes. With population-based and single-cell transcriptomics, we define a molecular time-lapse from pre-DC fate specification through DC niche formation and establish the developmental trajectory as the DC lineage emerges from fibroblasts. Co-expression of downregulated fibroblast and upregulated DC genes in niche precursors reveals a transitory molecular state following a proliferation shutdown. Waves of transcription factor and signaling molecule expression then coincide with DC formation. Finally, ablation of epidermal Wnt signaling and placode-derived FGF20 demonstrates their requirement for pre-DC specification. These findings uncover a progenitor-dependent niche precursor fate and the transitory molecular events controlling niche formation and function.

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Section: Discussionmentioning

confidence: 98%

Dermal Condensate Niche Fate Specification Occurs Prior to Formation and Is Placode Progenitor Dependent

et al. 2019

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“…Genetic ablation of Fgf20 has previously demonstrated its requirement for DC formation by hair follicle stage 1 through migration (Biggs et al, 2018;Huh et al, 2013), and furthermore here we show that FGF20 directly promotes the early DC niche fate. Similarly, recent identification of an Fgf20-expressing olfactory epithelial stem cell niche revealed a Wntregulated FGF20 requirement for formation of the underlying mesenchymal condensations that form nasal turbinates (Yang et al, 2018). Taken together these data indicate that the progenitors in nascent hair follicle pre-placodes signal to underlying fibroblasts at least in part through FGF20 to induce early DC fate prior to cluster-forming migration, and unequivocally demonstrate that progenitor fate precedes establishment of its supportive niche.…”

Section: Discussionmentioning

confidence: 67%

Fate Before Function: Specification of the Hair Follicle Niche Occurs Prior to its Formation and Is Progenitor Dependent

Mok

Saxena

Heitman

et al. 2018

Preprint

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Cell fate transitions are essential for specialization of stem cells and their niches, but the precise timing and sequence of molecular events during embryonic development are largely unknown. Here, we show that dermal condensates (DC), signaling niches for epithelial progenitors in hair placodes, are specified before niche formation and function. With 3D/4D microscopy we identify unclustered DC precursors. With population-based and single-cell transcriptomics we define a molecular time-lapse of dynamic niche signatures and the developmental trajectory as the DC lineage emerges from fibroblasts. Co-expression of downregulated fibroblast and upregulated DC genes in niche precursors reveals a transitory molecular state following a proliferation shutdown. Waves of transcription factor and signaling molecule expression then consolidate DC niche formation. Finally, ablation of epidermal Wnt signaling and placode-derived FGF20 demonstrates their requirement for DC-precursor specification. These findings uncover a progenitor-dependent niche precursor fate and the transitory molecular events controlling niche formation and function. and to Judith Vivié for expert assistance with single cell RNA sequencing at the Hubrecht Institute (Netherlands). Additionally, we thank Marja Mikkola (U. Helsinki) and Peggy Myung (Yale)) for helpful discussions and valuable comments. K.W.

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“…To confirm other genes identified by TRAPseq, we examined their expression patterns via ISH in Fgf20 -/+ ( Fgf20 Cre/+ ) and Fgf20 -/- ( Fgf20 Cre/βgal ) E14.5 cochleae. We began with DEGs that have been well-linked to FGF signaling (Table 4) and were downregulated in Fgf20 -/- cochleae by TRAPseq, such as Dusp6, Etv1, Spry1 , and Spry4 (Minowada et al 1999; Münchberg and Steinbeisser 1999; Willardsen et al 2014; Yang et al 2018). By ISH, Dusp6 (Dual specificity phosphatase 6) was expressed within the prosensory domain in control cochleae, and was almost undetectable in Fgf20 -/- cochleae (Fig.…”

Section: Resultsmentioning

confidence: 99%

Analysis of FGF20-regulated genes in organ of Corti progenitors by translating ribosome affinity purification

Yang¹,

Stout²,

Rauchman³

et al. 2020

Preprint

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BackgroundUnderstanding the mechanisms that regulate hair cell (HC) differentiation in the organ of Corti (OC) is essential to designing genetic therapies for hearing loss due to HC loss or damage. We have previously identified Fibroblast Growth Factor 20 (FGF20) as having a key role in HC and supporting cell differentiation in the mouse OC. To investigate the genetic landscape regulated by FGF20 signaling in OC progenitors, we employ Translating Ribosome Affinity Purification combined with Next Generation mRNA Sequencing (TRAPseq) in the Fgf20 lineage.ResultsWe show that TRAPseq targeting OC progenitors effectively enriched for mRNA within this rare cell population. TRAPseq identified differentially expressed genes downstream of FGF20, including Etv4, Etv5, Etv1, Dusp6, Hey1, Hey2, Heyl, Tectb, Fat3, Cpxm2, Sall1, Sall3, and cell cycle regulators such as Cdc20. Analysis of Cdc20 conditional-null mice identified decreased cochlea length, while analysis of Sall1-ΔZn2-10 mice, which harbor a mutation that causes Townes-Brocks syndrome, identified a decrease in outer hair cell number.ConclusionsWe present two datasets: genes with enriched expression in OC progenitors, and genes regulated by FGF20 in the embryonic day 14.5 cochlea. We validate select differentially expressed genes via in situ hybridization and in vivo functional studies in mice.Key findingsTranslating Ribosome Affinity Purification (TRAP) with Fgf20-Cre enriches for prosensory cell mRNATRAP combined with RNAseq identifies genes downstream of FGF20 during prosensory cell differentiationFGF20 regulates Sall1, gene implicated in human sensorineural hearing lossGrant Sponsor and NumberNational Institute on Deafness and Other Communication Disorders – DC017042 (DMO) Washington University Institute of Clinical and Translational Sciences and National Center for Advancing Translational Sciences – CTSA grant UL1TR002345 (JIT471 to DMO) March of Dimes – 6-FY13-127 (MR)

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FGF20-Expressing, Wnt-Responsive Olfactory Epithelial Progenitors Regulate Underlying Turbinate Growth to Optimize Surface Area

Cited by 28 publications

References 59 publications

Dermal Condensate Niche Fate Specification Occurs Prior to Formation and Is Placode Progenitor Dependent

Dermal Condensate Niche Fate Specification Occurs Prior to Formation and Is Placode Progenitor Dependent

Fate Before Function: Specification of the Hair Follicle Niche Occurs Prior to its Formation and Is Progenitor Dependent

Analysis of FGF20-regulated genes in organ of Corti progenitors by translating ribosome affinity purification

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