ABSTRACT
Differentiation of epithelial cells and morphogenesis of epithelial tubes or layers is closely linked with the establishment and remodeling of the apical junctional complex, which includes adherens junctions and tight junctions. Little is known about the transcriptional control of apical junctional complex components. Here, we show that the transcription factor grainyhead-like 2 (Grhl2), an epithelium-specific mammalian homolog of Drosophila Grainyhead, is essential for adequate expression of the adherens junction gene E-cadherin and the tight junction gene claudin 4 (Cldn4) in several types of epithelia, including gut endoderm, surface ectoderm and otic epithelium. We have generated Grhl2 mutant mice to demonstrate defective molecular composition of the apical junctional complex in these compartments that coincides with the occurrence of anterior and posterior neural tube defects. Mechanistically, we show that Grhl2 specifically associates with cis-regulatory elements localized at the Cldn4 core promoter and within intron 2 of the E-cadherin gene. Cldn4 promoter activity in epithelial cells is crucially dependent on the availability of Grhl2 and on the integrity of the Grhl2-associated cis-regulatory element. At the E-cadherin locus, the intronic Grhl2-associated cis-regulatory region contacts the promoter via chromatin looping, while loss of Grhl2 leads to a specific decrease of activating histone marks at the E-cadherin promoter. Together, our data provide evidence that Grhl2 acts as a target gene-associated transcriptional activator of apical junctional complex components and, thereby, crucially participates in epithelial differentiation.
Subject(s)
DNA-Binding Proteins/metabolism , Intercellular Junctions/chemistry , Transcription Factors/metabolism , Animals , Cadherins/metabolism , Cell Differentiation , Cell Line , Claudin-4 , Dogs , Epithelial Cells/cytology , Epithelial Cells/metabolism , Humans , Intercellular Junctions/metabolism , Membrane Proteins/genetics , Membrane Proteins/metabolism , Mice , Mice, Inbred C57BL , Transcription Factors/geneticsABSTRACT
The (pro)renin receptor is a protein that binds prorenin and renin in tissues, leading to their activation and, at the same time, to the initiation of intracellular signaling. The activation of local renin-angiotensin systems may play an important role in tissue damage induced by cardiovascular diseases and diabetes. However, (pro)renin receptor is also called ATP6ap2 because it has been shown to be associated with vacuolar H(+)-ATPase involvement in vesicular acidification and signaling in cells. Notably, lack of the protein in vertebrates leads to developmental alterations and early embryonic lethality probably as a result of the recently discovered role of the (pro)renin receptor and the vacuolar H(+)-ATPase in Wnt signaling. This review summarizes the current findings about these two functions of (pro)renin receptor/ATP6ap2 pointing out the possible links between both.
Subject(s)
Receptors, Cell Surface/metabolism , Renin/physiology , Vacuolar Proton-Translocating ATPases/metabolism , Wnt Proteins/metabolism , Adenosine Triphosphatases/metabolism , Animals , Cardiovascular Diseases/metabolism , Diabetes Mellitus/metabolism , Female , Humans , Male , Rats , Rats, Sprague-Dawley , Receptors, Cell Surface/antagonists & inhibitors , Receptors, Cell Surface/physiology , Renin/metabolism , Renin-Angiotensin System/physiology , Signal Transduction/physiology , Vacuolar Proton-Translocating ATPases/antagonists & inhibitors , Vacuolar Proton-Translocating ATPases/physiologyABSTRACT
Serotonin synthesis in mammals is initiated by 2 distinct tryptophan hydroxylases (TPH), TPH1 and TPH2. By genetically ablating TPH2, we created mice (Tph2(-/-)) that lack serotonin in the central nervous system. Surprisingly, these mice can be born and survive until adulthood. However, depletion of serotonin signaling in the brain leads to growth retardation and 50% lethality in the first 4 weeks of postnatal life. Telemetric monitoring revealed more extended daytime sleep, suppressed respiration, altered body temperature control, and decreased blood pressure (BP) and heart rate (HR) during nighttime in Tph2(-/-) mice. Moreover, Tph2(-/-) females, despite being fertile and producing milk, exhibit impaired maternal care leading to poor survival of their pups. These data confirm that the majority of central serotonin is generated by TPH2. TPH2-derived serotonin is involved in the regulation of behavior and autonomic pathways but is not essential for adult life.
