Germ cells are regulated by local microenvironments (niches), which secrete instructive cues. Conserved developmental signaling molecules act as niche-derived regulatory factors, yet other types of niche signals remain to be identified. Single-cell RNA-sequencing of sexual planarians revealed niche cells expressing a nonribosomal peptide synthetase ( nrps ). Inhibiting nrps led to loss of female reproductive organs and testis hyperplasia. Mass spectrometry detected the dipeptide β-alanyl-tryptamine (BATT), which is associated with reproductive system development and requires nrps and a monoamine-transmitter-synthetic enzyme Aromatic L-amino acid decarboxylase (AADC) for its production. Exogenous BATT rescued the reproductive defects after nrps or aadc inhibition, restoring fertility. Thus, a nonribosomal, monoamine-derived peptide provided by niche cells acts as a critical signal to trigger planarian reproductive development. These findings reveal an unexpected function for monoamines in niche-germ cell signaling. Furthermore, given the recently reported role for BATT as a male-derived factor required for reproductive maturation of female schistosomes, these results have important implications for the evolution of parasitic flatworms and suggest a potential role for nonribosomal peptides as signaling molecules in other organisms.

2002-12-01·Journal of Endocrinology3区 · 医学

Pharmacokinetics, safety and tolerability of three dosage regimens of buccal adhesive testosterone tablets in healthy men suppressed with leuprorelin

3区 · 医学

Article

作者: Boyce, M. J. ; Warrington, S. J. ; Pradhan, R. ; Bukofzer, S. ; Baisley, K. J.

We used a randomised, double-blind, crossover design to evaluate the pharmacokinetics, safety and tolerability of three doses of buccal adhesive testosterone tablets (BATT). Twenty-four healthy men, whose endogenous testosterone was suppressed to </=5.38 nmol/l with leuprorelin acetate, took BATT (10, 20 or 30 mg) daily for 10 days. There was a 4-day washout between treatments. Substantial testosterone absorption occurred from BATT, and mean serum testosterone, free testosterone and dihydrotestosterone (DHT) concentrations over 24 h showed circadian variation. Steady state was reached by day 5. Average 24-h concentrations for the three BATT doses were within the normal range for eugonadal men: testosterone 11.67-14.57 nmol/l, free testosterone 0.026-0.33 nmol/l and DHT 1.66-2.03 nmol/l. On all three doses, peak testosterone and free testosterone was reached 8-9 h after tablet application; DHT peaked about 1-2 h later, and declined more slowly. Hormone concentrations increased with BATT dose, but increases were less than dose-proportional. There was no evidence of testosterone accumulation. BATT was well tolerated.

A niche-derived non-ribosomal peptide triggers planarian sexual development

作者: Browder, Katherine L ; Issigonis, Melanie ; Newmark, Phillip A ; Chen, Rui ; Collins, James J

AbstractGerm cells are regulated by local microenvironments (niches), which secrete instructive cues. Conserved developmental signaling molecules act as niche-derived regulatory factors, yet other types of niche signals remain to be identified. Single-cell RNA-sequencing of sexual planarians revealed niche cells expressing a non-ribosomal peptide synthetase (nrps). Inhibitingnrpsled to loss of female reproductive organs and testis hyperplasia. Mass spectrometry detected the dipeptide β-alanyl-tryptamine (BATT), which is associated with reproductive system development and requiresnrpsand a monoamine-transmitter-synthetic enzyme (AADC) for its production. Exogenous BATT rescued the reproductive defects afternrpsoraadcinhibition, restoring fertility. Thus, a non-ribosomal, monoamine-derived peptide provided by niche cells acts as a critical signal to trigger planarian reproductive development. These findings reveal an unexpected function for monoamines in niche-germ cell signaling. Furthermore, given the recently reported role for BATT as a male-derived factor required for reproductive maturation of female schistosomes, these results have important implications for the evolution of parasitic flatworms and suggest a potential role for non-ribosomal peptides as signaling molecules in other organisms.

100 项与 BATT(Ghent University Hospital) 相关的药物交易

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