Biology subjects

Barlow, L. A.

Publications and source records attributed to Barlow, L. A..

4 recordsLinked to original sources

bioRxiv2025

Tyrosine kinase inhibitors affect sweet taste and dysregulate fate selection of specific taste cell subtypes via KIT inhibition.

Taste dysfunction, or dysgeusia, is a common side effect of many cancer drugs. Dysgeusia is often reported by patients treated with anti-angiogenic tyrosine kinase inhibitors (TKIs), which inhibit receptor tyrosine kinases (RTKs). However, the mechanisms by which TKIs cause dysgeusia are not understood, as the role of RTKs in adult taste homeostasis is unknown. Here, we find that treating adult mice with the TKI cabozantinib shifts the fate of differentiating functional taste cell subtypes within taste buds. Through behavioral assays, we find this cell fate shift leads to blunted responses to sweet in cabozantinib-treated mice. Finally, we show that inducible knockout of the RTK KIT, which is inhibited by cabozantinib, phenocopies taste cell fate shifts induced by TKI treatment. Our results establish KIT as a regulator of taste cell homeostasis and suggest that KIT inhibition may underlie TKI-induced dysgeusia in patients. SummaryKIT signaling blockade by tyrosine kinase inhibitors alters the fate of functional taste bud cell subtypes.

neuroscience↗

bioRxiv2022

High Sox2 expression predicts taste lineage competency of lingual progenitors in vitro.

SO_SCPLOWUMMARYC_SCPLOWTaste buds on the tongue are collections of taste receptor cells (TRCs) that detect sweet, sour, salty, umami and bitter stimuli. Like non-taste lingual epithelium, TRCs are renewed from basal keratinocytes, many of which express the transcription factor SOX2. Genetic lineage tracing has shown SOX2+ lingual progenitors give rise to both taste and non-taste lingual epithelium in the posterior circumvallate taste papilla (CVP) of mice. However, SOX2 is variably expressed among CVP cells suggesting that their progenitor potential may vary. Using transcriptome analysis and organoid technology, we show highly expressing SOX2+ cells are taste-competent progenitors that give rise to organoids comprising both TRCs and lingual epithelium, while organoids derived from low-expressing SOX2+ progenitors are composed entirely of non-taste cells. Hedgehog and WNT/{beta}-catenin are required for taste homeostasis in adult mice, but only WNT/{beta}-catenin promotes TRC differentiation in vitro and does so only in organoids derived from higher SOX2+ taste lineage-competent progenitors.

developmental biology↗

bioRxiv2020

Onset of taste bud cell renewal starts at birth and coincides with a shift in SHH function.

Embryonic taste bud primordia are specified as taste placodes on the tongue surface and differentiate into the first taste receptor cells (TRCs) at birth. Throughout adult life, TRCs are continually regenerated from epithelial progenitors. Sonic hedgehog (SHH) signaling regulates TRC development and renewal, repressing taste fate embryonically, but promoting TRC differentiation in adults. Here we show TRC renewal initiates at birth and coincides with onset of SHHs pro-taste function. Using transcriptional profiling to explore molecular regulators of renewal, we identified Foxa1 and Foxa2 as potential SHH target genes in lingual progenitors at birth, and show SHH overexpression in vivo alters FOXA1 and FOXA2 expression relevant to taste buds. We further bioinformatically identify genes relevant to cell adhesion and cell locomotion likely regulated by FOXA1;FOXA2, and show expression of these candidates is also altered by forced SHH expression. We present a new model where SHH promotes TRC differentiation by regulating changes in epithelial cell adhesion and migration.

developmental biology↗

bioRxiv2018

SOX2 Regulation by Hedgehog Signaling Controls Adult Lingual Epithelium Homeostasis

The adult tongue epithelium is continuously renewed from epithelial progenitor cells, and this process relies on intact Hedgehog (HH) signaling. In mice, inhibition of the HH pathway using Smoothened antagonists (HH pathway inhibitors or HPIs) leads to taste bud loss over a span of several weeks. Previously, we demonstrated that overexpression of Sonic Hedgehog (SHH) in lingual epithelial progenitors induces formation of ectopic taste buds accompanied by locally increased SOX2 expression, consistent with the hypothesis that taste bud differentiation depends on SOX2 downstream of HH. To test this idea, we inhibited HH signaling by treating SOX2-GFP mice with HPI and found a rapid and drastic decline in SOX2-GFP expression in taste progenitors and taste buds. Using a conditional Cre-lox system to delete Sox2, we found that loss of SOX2 blocks differentiation of both taste buds and non-taste epithelium that comprises the majority of the tongue surface; progenitor cells increase in number at the expense of differentiated taste cells and lingual keratinocytes. In contrast to the normal pattern of basally restricted proliferation, dividing cells are overabundant, disorganized and present in suprabasal epithelial layers in Sox2 deleted tongues. Additionally, SOX2 loss in taste progenitors leads non-cell autonomously to rapid loss of taste bud cells via apoptosis, dramatically shortening taste cell lifespans. Finally, when Sox2 is conditionally deleted in mice with constitutive overexpression of SHH, ectopic taste buds fail to form and endogenous taste buds disappear; instead, robust hyperproliferation takes over the entire lingual epithelium. In sum, our experiments suggest that SOX2 functions downstream of HH signaling to regulate lingual epithelium homeostasis.

developmental biology↗