The first lineage specification of pluripotent mouse epiblast segregates neuroectoderm (NE) from mesoderm and endoderm (ME) by currently poorly understood mechanisms. Here we demonstrate that the induction of any ME-gene programs critically relies on the T-box (Tbx) transcription factors Eomes and Brachyury that concomitantly repress pluripotency and NE gene programs. Tbx-deficient cells retain pluripotency and differentiate to NE lineages despite the presence of ME-inducing signals TGFb/Nodal and WNT. Pluripotency and NE gene networks are additionally repressed by Tbx-induced ME factors, demonstrating a remarkable redundancy in program regulation to safeguard mutually exclusive lineage specification. Chromatin analyses revealed that accessibility of ME-gene enhancers depends on Tbx-binding, while NE-gene enhancers are accessible and activation-primed already at pluripotency state. This asymmetry of chromatin landscape thus explains the default differentiation of pluripotent cells to NE in the absence of MEinduction mediated through the activating and repressive functions of early Tbx factors Eomes and Brachyury.
Polycystic kidney disease (PKD) and other renal ciliopathies are characterized by cysts, inflammation, and fibrosis. Cilia function as signaling centers, but a molecular link to inflammation in the kidney has not been established. Here, we show that cilia in renal epithelia activate chemokine signaling to recruit inflammatory cells. We identify a complex of the ciliary kinase LKB1 and several ciliopathy‐related proteins including NPHP1 and PKD1. At homeostasis, this ciliary module suppresses expression of the chemokine CCL2 in tubular epithelial cells. Deletion of LKB1 or PKD1 in mouse renal tubules elevates CCL2 expression in a cell‐autonomous manner and results in peritubular accumulation of CCR2+ mononuclear phagocytes, promoting a ciliopathy phenotype. Our findings establish an epithelial organelle, the cilium, as a gatekeeper of tissue immune cell numbers. This represents an unexpected disease mechanism for renal ciliopathies and establishes a new model for how epithelial cells regulate immune cells to affect tissue homeostasis.
General rightsThis document is made available in accordance with publisher policies. Please cite only the published version using the reference above. We propose that the promoter mutation alters tissue-specific chromatin loop formation with consequent organ-specific deficiency of PMM2 leading to the restricted phenotype of HIPKD. Our findings extend the spectrum of genetic 5 causes for both HI and PKD and provide insights into gene regulation and PMM2 pleiotropy.6
BackgroundSperm have but one purpose, to fertilize an egg. In various species including
Drosophila melanogaster female sperm storage is a
necessary step in the reproductive process. Amo is a homolog of the human
transient receptor potential channel TRPP2 (also known as PKD2), which is
mutated in autosomal dominant polycystic kidney disease. In flies Amo is
required for sperm storage. Drosophila males with Amo
mutations produce motile sperm that are transferred to the uterus but they
do not reach the female storage organs. Therefore Amo appears to be a
mediator of directed sperm motility in the female reproductive tract but the
underlying mechanism is unknown.Methodology/Principal FindingsAmo exhibits a unique expression pattern during spermatogenesis. In
spermatocytes, Amo is restricted to the endoplasmic reticulum (ER) whereas
in mature sperm, Amo clusters at the distal tip of the sperm tail. Here we
show that flagellar localization of Amo is required for sperm storage. This
raised the question of how Amo at the rear end of sperm regulates forward
movement into the storage organs. In order to address this question, we used
in vivo imaging of dual labelled sperm to demonstrate
that Drosophila sperm navigate backwards in the female
reproductive tract. In addition, we show that sperm exhibit hyperactivation
upon transfer to the uterus. Amo mutant sperm remain
capable of reverse motility but fail to display hyperactivation and directed
movement, suggesting that these functions are required for sperm storage in
flies.Conclusions/SignificanceAmo is part of a signalling complex at the leading edge of the sperm tail
that modulates flagellar beating and that guides a backwards path into the
storage organs. Our data support an evolutionarily conserved role for TRPP2
channels in cilia.
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