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Rosettes are widely used in epithelial morphogenesis during embryonic development and organogenesis. However, their role in postnatal development and adult tissue maintenance remains largely unknown. Here, we show zona glomerulosa cells in the adult adrenal cortex organize into rosettes through adherens junction-mediated constriction, and that rosette formation underlies the maturation of adrenal glomerular structure postnatally. Using genetic mouse models, we show loss of β-catenin results in disrupted adherens junctions, reduced rosette number, and dysmorphic glomeruli, whereas β-catenin stabilization leads to increased adherens junction abundance, more rosettes, and glomerular expansion. Furthermore, we uncover numerous known regulators of epithelial morphogenesis enriched in β-catenin-stabilized adrenals. Among these genes, we show Fgfr2 is required for adrenal rosette formation by regulating adherens junction abundance and aggregation. Together, our data provide an example of rosette-mediated postnatal tissue morphogenesis and a framework for studying the role of rosettes in adult zona glomerulosa tissue maintenance and function. Multicellular rosettes are known to mediate complex cellular reorganization such as epithelial folding and branching during embryonal organogenesis. Here the authors show that rosette formation regulated by β-Catenin and FGFR2 mediate postnatal adrenal cortex zona glomerulosa morphogenesis.

Adrenocortical carcinoma (ACC) is a rare and aggressive malignancy with limited therapeutic options. The lack of mouse models that recapitulate the genetics of ACC has hampered progress in the field. We analyzed The Cancer Genome Atlas (TCGA) dataset for ACC and found that patients harboring alterations in both p53/Rb and Wnt/β-catenin signaling pathways show a worse prognosis compared with patients that harbored alterations in only one. To model this, we utilized the Cyp11b2(AS)Cre mouse line to generate mice with adrenocortical-specific Wnt/β-catenin activation, Trp53 deletion, or the combination of both. Mice with targeted Wnt/β-catenin activation or Trp53 deletion showed no changes associated with tumor formation. In contrast, alterations in both pathways led to ACC with pulmonary metastases. Similar to ACCs in humans, these tumors produced increased levels of corticosterone and aldosterone and showed a high proliferation index. Gene expression analysis revealed that mouse tumors exhibited downregulation of Star and Cyp11b1 and upregulation of Ezh2, similar to ACC patients with a poor prognosis. Altogether, these data show that altering both Wnt/β-catenin and p53/Rb signaling is sufficient to drive ACC in mouse. This autochthonous model of ACC represents a new tool to investigate the biology of ACC and to identify new treatment strategies.

Unsuppressed hepatic glucose production (HGP) contributes substantially to glucose intolerance and diabetes, which can be modeled by the genetic inactivation of hepatic insulin receptor substrate 1 ( Irs1 ) and Irs2 (LDKO mice). We previously showed that glucose intolerance in LDKO mice is resolved by hepatic inactivation of the transcription factor FoxO1 (that is, LTKO mice)—even though the liver remains insensitive to insulin. Here, we report that insulin sensitivity in the white adipose tissue of LDKO mice is also impaired but is restored in LTKO mice in conjunction with normal suppression of HGP by insulin. To establish the mechanism by which white adipose tissue insulin signaling and HGP was regulated by hepatic FoxO1, we identified putative hepatokines—including excess follistatin (Fst)—that were dysregulated in LDKO mice but normalized in LTKO mice. Knockdown of hepatic Fst in the LDKO mouse liver restored glucose tolerance, white adipose tissue insulin signaling and the suppression of HGP by insulin; however, the expression of Fst in the liver of healthy LTKO mice had the opposite effect. Of potential clinical significance, knockdown of Fst also improved glucose tolerance in high-fat-fed obese mice, and the level of serum Fst was reduced in parallel with glycated hemoglobin in obese individuals with diabetes who underwent therapeutic gastric bypass surgery. We conclude that Fst is a pathological hepatokine that might be targeted for diabetes therapy during hepatic insulin resistance. Follistatin acts as a hepatokine to induce insulin resistance and can be targeted to improve diabetes in mice.

Aldosterone-producing zona glomerulosa (zG) cells of the adrenal gland arrange in distinct multi-cellular rosettes that provide a structural framework for adrenal cortex morphogenesis and plasticity. Whether this cyto-architecture also plays functional roles in signaling remains unexplored. To determine if structure informs function, we generated mice with zG-specific expression of GCaMP3 and imaged zG cells within their native rosette structure. Here we demonstrate that within the rosette, angiotensin II evokes periodic Ca v 3-dependent calcium events that form bursts that are stereotypic in form. Our data reveal a critical role for angiotensin II in regulating burst occurrence, and a multifunctional role for the rosette structure in activity-prolongation and coordination. Combined our data define the calcium burst as the fundamental unit of zG layer activity evoked by angiotensin II and highlight a novel role for the rosette as a facilitator of cell communication. Aldosterone-producing zona glomerulosa cells in the adrenal gland arrange into rosette structures known to be important for morphogenesis. Here the authors show that the cells in the rosettes produce coordinated calcium activity bursts in response to angiotensin II that correlate with aldosterone production level.

This single-centre, open-label, randomised, parallel-group study assessed the acceptability, swallowability, palatability, and safety of film-coated, 3 mm diameter mini-tablets in children aged ≥2–<7 years. In total, 300 participants were randomised (2:2:1:1) to receive a single oral administration of 16 (group A) or 32 (group B) mini-tablets with soft food or 16 (group C) or 32 (group D) mini-tablets with water. Children in each group were stratified by age group (2–<3 years; 3–<4 years; 4–<5 years; 5–<6 years; and 6–<7 years). Groups C and D were pooled for statistical analyses. The rates of acceptability (swallowed ≥80% of the mini-tablets with or without chewing), swallowability (swallowed all mini-tablets without chewing or any leftover), and palatability (positive/neutral responses) were ≥80.0%, ≥42.0%, and ≥82.0%, respectively, across the study groups. No marked differences were observed between groups or across age groups. No adverse events or issues of clinical relevance with deglutition were reported. Mini-tablets taken with soft food or water provide a suitable method for administering medicines to children aged ≥2–<7 years. This study was registered in the German Clinical Trial Register (No. DRKS00024617).

Agriculture has supported human life from the beginning of civilization, despite a plethora of biotic (pests, pathogens) and abiotic (drought, cold) stressors being exerted on the global food demand. In the past 50 years, the enhanced understanding of cellular and molecular mechanisms in plants has led to novel innovations in biotechnology, resulting in the introduction of desired genes/traits through plant genetic engineering. Targeted genome editing technologies such as Zinc-Finger Nucleases (ZFNs), Transcription Activator-Like Effector Nucleases (TALENs), and Clustered Regularly Interspaced Short Palindromic Repeats (CRISPR) have emerged as powerful tools for crop improvement. This new CRISPR technology is proving to be an efficient and straightforward process with low cost. It possesses applicability across most plant species, targets multiple genes, and is being used to engineer plant metabolic pathways to create resistance to pathogens and abiotic stressors. These novel genome editing (GE) technologies are poised to meet the UN’s sustainable development goals of “zero hunger” and “good human health and wellbeing.” These technologies could be more efficient in developing transgenic crops and aid in speeding up the regulatory approvals and risk assessments conducted by the US Departments of Agriculture (USDA), Food and Drug Administration (FDA), and Environmental Protection Agency (EPA).

The mineralocorticoid aldosterone, secreted by the adrenal zona glomerulosa (ZG), is critical for life, maintaining ion homeostasis and blood pressure. Therapeutic inhibition of protein phosphatase 3 (calcineurin, Cn) results in inappropriately low plasma aldosterone levels despite concomitant hyperkalemia and hyperreninemia. We tested the hypothesis that Cn participates in the signal transduction pathway regulating aldosterone synthesis. Inhibition of Cn with tacrolimus abolished the potassium-stimulated (K + -stimulated) expression of aldosterone synthase, encoded by CYP11B2 , in the NCI-H295R human adrenocortical cell line as well as ex vivo in mouse and human adrenal tissue. ZG-specific deletion of the regulatory Cn subunit CnB1 diminished Cyp11b2 expression in vivo and disrupted K + -mediated aldosterone synthesis. Phosphoproteomics analysis identified nuclear factor of activated T cells, cytoplasmic 4 (NFATC4), as a target for Cn-mediated dephosphorylation. Deletion of NFATC4 impaired K + -dependent stimulation of CYP11B2 expression and aldosterone production while expression of a constitutively active form of NFATC4 increased expression of CYP11B2 in NCI-H295R cells. Chromatin immunoprecipitation revealed NFATC4 directly regulated CYP11B2 expression. Thus, Cn controls aldosterone production via the Cn/NFATC4 pathway. Inhibition of Cn/NFATC4 signaling may explain low plasma aldosterone levels and hyperkalemia in patients treated with tacrolimus, and the Cn/NFATC4 pathway may provide novel molecular targets to treat primary aldosteronism.

How morphology informs function has long been a topic of fascination in biology. In an adult organ, highly specialized cell types function together in microenvironments that are often drastically different depending on the anatomical location of the organ. However, little is known about how different morphological features can influence diverse cellular functions. The adrenal cortex is an ideal model to study this question. As part of the mammalian endocrine system, the adult cortex consists of concentric layers of tissue termed “zones”. Each zone produces distinct steroid hormones and adopts a unique morphology. The mechanisms governing the formation of these morphological features and their functional significance are unknown.In this dissertation, we first examine the morphological features of the outer layer, zona glomerulosa (zG), and identify cellular and molecular mechanisms governing its formation. We show mature adrenal glomeruli consist of rosettes, a multicellular structure widely used in epithelial remodeling during development. Furthermore, rosette formation underlies a previously unknown process of postnatal glomerular morphogenesis. β-catenin, an integral component of the adherens junction and key transducer of canonical WNT signaling, is a potent regulator of glomerular morphology. β-catenin stabilization leads to increased FGFR2. Deletion of Fgfr2 results in altered adherens junction stability and distribution, leading to decreased rosette frequency and disruption of glomerular morphology.Next, we investigate the impact of WNT and FGF signaling modulation on zG physiological function. β-catenin stabilization causes zG hyperplasia due to a block of zonal transdifferentiation, concurrent with increased aldosterone and elevated blood pressure. In contrast, Fgfr2 deletion results in suppressed zG function, as evident by loss of Cyp11b2 expression and increased plasma renin activity, a compensatory response to insufficient aldosterone output. Moreover, pharmacological inhibition of FGFR2 effectively lowers aldosterone production and zG proliferation, demonstrating the therapeutic potential of FGFR2 inhibition in treating hyperaldosteronism and adrenal hyperplasia.Together, this dissertation provides fundamental insights into how the adrenal zG acquires its form. We show the WNT and FGF signaling pathways are important regulators of zG morphology and function. Our findings provide a conceptual framework for future studies on the link between zG tissue morphology and function.

Fibroblast growth factor receptors (FGFRs) are tyrosine kinase receptors critical for organogenesis and tissue maintenance, including in the adrenal gland. Here we delineate the role of FGFR2 in the morphogenesis, maintenance, and function of the adrenal cortex with a focus on the zona glomerulosa (zG). zG-specific Fgfr2 deletion (Fgfr2-cKO) resulted in impaired zG cell identity, proliferation, and transdifferentiation into zona fasciculata (zF) cells during postnatal development. In adult mice, induced deletion of Fgfr2 led to loss of mature zG cell identity, highlighting the importance of FGFR2 for the maintenance of a differentiated zG state. Strikingly, Fgfr2-cKO was sufficient to fully abrogate β-catenin–induced zG hyperplasia and to reduce aldosterone levels. Finally, short-term treatment with pan-FGFR small molecule inhibitors suppressed aldosterone production in both WT and β-catenin gain-of-function mice. These results demonstrate a critical role for FGFR signaling in adrenal morphogenesis, maintenance, and function and suggest that targeting FGFR signaling may benefit patients with aldosterone excess and/or adrenal hyperplasia.

In the version of this article originally published, the y axis labels in Fig. 4b,d were incorrect. In Fig. 4b, the unit on the label was (ng mg –1 ). This should have been (ng/ml). In Fig. 4d, the y axis label was Serum Fst (ng ml –1 ). It should have been Serum insulin (ng/ml). The errors have been corrected in the HTML and PDF versions of this article.