RDH10-mediated retinol metabolism and RARα-mediated retinoic acid signaling are required for submandibular salivary gland initiation

Metzler, Melissa A.; Raja, Swetha; Elliott, Kelsey H.; Friedl, Regina; Tran, Nhut Quang Huy; Brugmann, Samantha A.; Larsen, Melinda; Sandell, Lisa L.

doi:10.1242/dev.164822

Cited by 24 publications

(24 citation statements)

References 69 publications

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“…Interestingly, RDH10 also expressed in cluster 9 (Supplementary Fig. S3b ), which is essential for the production of RA 27 . On the other hand, transcription factors were clustered across granulosa cell subpopulations (Fig.…”

Section: Resultsmentioning

confidence: 99%

Single-cell RNA sequencing reveals regulation of fetal ovary development in the monkey (Macaca fascicularis)

Zhao

Meng

et al. 2020

Cell Discov

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Germ cells are vital for reproduction and heredity. However, the mechanisms underlying female germ cell development in primates, especially in late embryonic stages, remain elusive. Here, we performed single-cell RNA sequencing of 12,471 cells from whole fetal ovaries, and explored the communications between germ cells and niche cells. We depicted the two waves of oogenesis at single-cell resolution and demonstrated that progenitor theca cells exhibit similar characteristics to Leydig cells in fetal monkey ovaries. Notably, we found that ZGLP1 displays differentially expressed patterns between mouse and monkey, which is not overlapped with NANOG in monkey germ cells, suggesting its role in meiosis entry but not in activating oogenic program in primates. Furthermore, the majority of germ cell clusters that sharply express PRDM9 and SPO11 might undergo apoptosis after cyst breakdown, leading to germ cell attrition. Overall, our work provides new insights into the molecular and cellular basis of primate fetal ovary development at single-cell resolution.

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Section: Resultsmentioning

confidence: 99%

Single-cell RNA sequencing reveals regulation of fetal ovary development in the monkey (Macaca fascicularis)

Zhao

Meng

et al. 2020

Cell Discov

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“…In the current study, we utilize the same mouse strains to conditionally inactivate RDH10 function by administration of tamoxifen at E8.5. These experimental conditions, with tamoxifen administered at E8.5, have been previously validated to completely eliminate Rdh10 RNA by E10.5, which attenuates RA signaling activity to 30% that of control embryos by E11.5 (Metzler et al, 2018). It is important to note that, using the ubiquitously expressed Cre-ERT2, the genotype of embryos with a floxed allele changes following administration of tamoxifen.…”

Section: Resultsmentioning

confidence: 98%

“…For the Rdh10 conditional mutant system used in this study (administered tamoxifen at E8.5), we have previously quantified the overall whole-embryo level of RA signaling activity in mutant embryos to be 30% that of control littermates at E11.5 (Metzler et al, 2018). Here, we use the RARE- lacZ reporter transgene to assess the spatial distribution of RA signaling activity within the pharyngeal region at E10.5 (Fig.…”

Section: Resultsmentioning

confidence: 99%

RDH10 function is necessary for spontaneous fetal mouth movement that facilitates palate shelf elevation

Friedl

Raja

Metzler

et al. 2019

Disease Models &Amp; Mechanisms

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Cleft palate is a common birth defect, occurring in approximately 1 in 1000 live births worldwide. Known etiological mechanisms of cleft palate include defects within developing palate shelf tissues, defects in mandibular growth and defects in spontaneous fetal mouth movement. Until now, experimental studies directly documenting fetal mouth immobility as an underlying cause of cleft palate have been limited to models lacking neurotransmission. This study extends the range of anomalies directly demonstrated to have fetal mouth movement defects correlated with cleft palate. Here, we show that mouse embryos deficient in retinoic acid (RA) have mispatterned pharyngeal nerves and skeletal elements that block spontaneous fetal mouth movement in utero . Using X-ray microtomography, in utero ultrasound video, ex vivo culture and tissue staining, we demonstrate that proper retinoid signaling and pharyngeal patterning are crucial for the fetal mouth movement needed for palate formation. Embryos with deficient retinoid signaling were generated by stage-specific inactivation of retinol dehydrogenase 10 ( Rdh10 ), a gene crucial for the production of RA during embryogenesis. The finding that cleft palate in retinoid deficiency results from a lack of fetal mouth movement might help elucidate cleft palate etiology and improve early diagnosis in human disorders involving defects of pharyngeal development.

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“…Thus, given that SFB protects against C. rodentium infection ( Figure 1A), we hypothesized that RA may mediate SFB-dependent defense against this pathogen. In order to test whether SFB promotes protection to infection by activating RAR, GF and SFB-colonized mice were treated with an RAR-inverse agonist (RARi: BMS493) ( Figure 4G) that blocks RA-RAR activation (Metzler et al, 2018). RARi treatment did not alter SFB colonization ( Figure 4H).…”

Section: Commensal Bacteria Provide a Direct Source Of Retinoic Acid mentioning

confidence: 99%

Commensal bacterial-derived retinoic acid primes host defense to intestinal infection

Woo

Eshleman

Whitt

et al. 2021

Preprint

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SummaryInteractions between the microbiota and mammalian host are essential for effective defense against pathogenic infection; however, the microbial-derived cues that mediate this beneficial relationship remain unclear. Here, we find that the intestinal epithelial cell (IEC)-associated commensal bacteria, Segmented Filamentous Bacteria (SFB), promotes early protection against the bacterial pathogen, Citrobacter rodentium, independently of CD4+ T cells. Global analyses demonstrated that SFB induced histone modifications in IECs at sites enriched for the retinoic acid receptor (RAR) motif. Interestingly, SFB-colonized mice exhibited greater expression of RAR targets during infection relative to germ-free mice, suggesting SFB may enhance defense through retinoic acid (RA) signaling. Consistent with this, supplementing germ-free mice with RA decreased pathogen levels. Further, mice with impaired RA-responsiveness in IECs displayed increased susceptibility to C. rodentium infection. RA was elevated in the intestine of mice colonized with SFB, indicating that the presence of commensal bacteria can modulate intestinal RA levels. However, this regulation by SFB was not dependent on mammalian RA production. Sequence analyses suggested that RA-generating enzymes are expressed by a subset of commensal bacteria. Remarkably, RA was produced by intestinal bacteria including SFB, and inhibiting RA signaling blocked SFB-induced protection against C. rodentium infection. These data collectively reveal RA as an unexpected microbiota-derived metabolite that primes innate intestinal defense and suggests that pre- and probiotic approaches to elevate RA could prevent or combat pathogenic infection.

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RDH10-mediated retinol metabolism and RARα-mediated retinoic acid signaling are required for submandibular salivary gland initiation

Cited by 24 publications

References 69 publications

Single-cell RNA sequencing reveals regulation of fetal ovary development in the monkey (Macaca fascicularis)

Single-cell RNA sequencing reveals regulation of fetal ovary development in the monkey (Macaca fascicularis)

RDH10 function is necessary for spontaneous fetal mouth movement that facilitates palate shelf elevation

Commensal bacterial-derived retinoic acid primes host defense to intestinal infection

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