Creating leadership collectives for sustainability transformations.

Enduring sustainability challenges requires a new model of collective leadership that embraces critical reflection, inclusivity and care. Leadership collectives can support a move in academia from metrics to merits, from a focus on career to care, and enact a shift from disciplinary to inter- and trans-disciplinary research. Academic organisations need to reorient their training programs, work ethics and reward systems to encourage collective excellence and to allow space for future leaders to develop and enact a radically re-imagined vision of how to lead as a collective with care for people and the planet. SUPPLEMENTARY INFORMATION: The online version contains supplementary material available at 10.1007/s11625-021-00909-y.

The RET-glial cell-derived neurotrophic factor (GDNF) pathway stimulates migration and chemoattraction of epithelial cells.

Embryonic development requires cell migration in response to positional cues. Yet, how groups of cells recognize and translate positional information into morphogenetic movement remains poorly understood. In the developing kidney, the ureteric bud epithelium grows from the nephric duct towards a group of posterior intermediate mesodermal cells, the metanephric mesenchyme, and induces the formation of the adult kidney. The secreted protein GDNF and its receptor RET are required for ureteric bud outgrowth and subsequent branching. However, it is unclear whether the GDNF-RET pathway regulates cell migration, proliferation, survival, or chemotaxis. In this report, we have used the MDCK renal epithelial cell line to show that activation of the RET pathway results in increased cell motility, dissociation of cell adhesion, and the migration towards a localized source of GDNF. Cellular responses to RET activation include the formation of lamellipodia, filopodia, and reorganization of the actin cytoskeleton. These data demonstrate that GDNF is a chemoattractant for RET-expressing epithelial cells and thus account for the developmental defects observed in RET and GDNF mutant mice. Furthermore, the RET-transfected MDCK cells described in this report are a promising model for delineating RET signaling pathways in the renal epithelial cell lineage.

Another niche for Notch.

The Notch signaling pathway patterns the developing nephron along the proximal-distal axis during renal development. In an adult acute tubular necrosis model, Kobayashi et al. now show expression of many Notch components and the activation of Notch target genes, suggesting a critical function for Notch in regenerating proximal tubules.

The regulation of kidney development: new insights from an old model.

The embryonic kidney is an excellent model system in which to address many fundamental issues in developmental biology. Inductive interactions are required for proliferation and differentiation of the ureter epithelium and kidney mesenchyme. Recent studies implicate a receptor-type tyrosine kinase as a target of inductive signals in the developing ureter. In the mesenchyme, the early induction response requires at least two transcription factors, WT1 and Pax-2. Through the integrated application of in vitro culture models and gene targeting methods, the molecular mechanisms underlying kidney morphogenesis are becoming clearer.

Intercellular signalling. The pros and cons of c-ret.

Recent studies of the proto-oncogene c-ret illuminate the basic developmental signalling pathways mediated by receptor tyrosine kinases, as well as the aberrant signalling processes that can lead to cancer.

The PAX2 tanscription factor is expressed in cystic and hyperproliferative dysplastic epithelia in human kidney malformations.

Human dysplastic kidneys are developmental aberrations which are responsible for many of the very young children with chronic renal failure. They contain poorly differentiated metanephric cells in addition to metaplastic elements. We recently demonstrated that apoptosis was prominent in undifferentiated cells around dysplastic tubules (Winyard, P.J.D., J. Nauta, D.S. Lirenman, P. Hardman, V.R. Sams, R.A. Risdon, and A.S. Woolf. 1996. Kidney Int. 49:135-146), perhaps explaining the tendency of some of these organs to regress. In contrast, apoptosis was rare in dysplastic epithelia which are thought to be ureteric bud malformations. On occasion, these tubules form cysts which distend the abdominal cavity (the multicystic dysplastic kidney) and dysplastic kidneys may rarely become malignant. We now demonstrate that dysplastic tubules maintain a high rate of proliferation postnatally and that PAX2, a potentially oncogenic transcription factor, is expressed in these epithelia. In contrast, both cell proliferation and PAX2 are downregulated during normal maturation of human collecting ducts. We demonstrate that BCL2, a protein which prevents apoptosis in renal mesenchymal to epithelia] conversion, is expressed ectopically in dysplastic kidney epithelia. We propose that dysplastic cyst formation may be understood in terms of aberrant temporal and spatial expression of master genes which are tightly regulated in the normal program of human nephrogenesis.

PTIP, a novel BRCT domain-containing protein interacts with Pax2 and is associated with active chromatin.

The Pax gene family encodes transcription factors essential for organ and tissue development in higher eukaryotes. Pax proteins are modular with an N-terminal DNA binding domain, a C-terminal transcription activation domain, and a transcription repression domain called the octapeptide. How these domains interact with the cellular machinery remains unclear. In this report, we describe the isolation and characterization of a novel gene and its encoded protein, PTIP, which binds to the activation domain of Pax2 and other Pax proteins. PTIP binds to Pax2 in vitro, in the yeast two-hybrid assay and in tissue culture cells. The binding of PTIP to Pax2 is inhibited by the octapeptide repression domain. The PTIP protein contains five BRCT domains, first identified in BRCA1 and other nuclear proteins involved in DNA repair/recombination or cell cycle control. Pax2 and PTIP co-localize in the cell nucleus to actively expressed chromatin and the nuclear matrix fraction. For the first time, these results point to a link between Pax transcription factors and active chromatin.

Expression of Pax-2 in human renal cell carcinoma and growth inhibition by antisense oligonucleotides.

Renal cell carcinoma (RCC) is the most common malignancy in the adult kidney. Because RCC is generally thought to arise from the epithelium of the proximal tubules, the expression of Pax-2, a gene required for renal epithelium development, was examined in primary tumors and tumor-derived cell lines. Immunostaining of frozen sections from the primary tumors indicated Pax-2 expression in the malignant cells but not in the surrounding stroma. In a panel of human RCC-derived cell lines, 73% expressed Pax-2 protein and mRNA. Treatment of RCC cell lines with antisense oligodeoxynucleotides resulted in down-regulation of Pax-2 protein expression and growth inhibition after 3 days in culture. These data indicate that Pax-2 gene function is required for proliferation, as well as differentiation during embryonic development, and suggest a novel therapy for RCC.

The paired-box transcription factor, PAX2, positively modulates expression of the Wilms' tumor suppressor gene (WT1).

The Wilms' tumor suppressor gene, wt1, encodes a zinc finger protein which functions as a transcriptional regulator. Expression of the wt1 gene is developmentally regulated and restricted to a small set of tissues which include the fetal urogenital system, mesothelium, and spleen. In the developing kidney, induction of neprohogenesis by the ureter is accompanied by an increase in expression levels of the Pax-2 gene, a developmentally and spatially regulated paired-box member. This is followed by an increase in wt1 expression as mesenchymal cells condense and differentiate. In this report, we demonstrate that PAX2 isoforms are capable of transactivating the wt1 promoter. Deletion mutagenesis of the wt1 promoter identified an element responsible for mediating PAX2 responsiveness, located between nucleotides -33 and -71 relative to the first wt1 transcription start site. Consistent with its identity as a PAX responsive element, multimerization of this mofit upstream of a heterologous minimal promoter enhanced reporter activity when co-transfected with a Pax-2 expression vector. Finally, we demonstrate that PAX2 can stimulate expression of the endogenous wt1 gene. These results suggest that a role for PAX2 during mesenchyme-to-epithelium transition in renal development is to induce wt1 expression.

TCF-4 binds beta-catenin and is expressed in distinct regions of the embryonic brain and limbs.

The Tcf family of transcription factors, in association with beta-catenin, mediate Wnt signaling by transactivating downstream target genes. Given the function of wnt genes in neural development and organogenesis, Tcf transcription factors must be integral to the development of many embryonic tissues. In fact, the role of Tcf genes in axis formation in Xenopus and in segment polarity in Drosophila is well established. In this report, we have identified two isoforms of the mouse Tcf-4 gene. Tcf-4 expressing cells showed nuclear localization of beta-catenin. Although Tcf-4 RNA was widely distributed throughout embryogenesis, high levels of Tcf-4 expression were particularly evident in the developing CNS and limb buds. In extended streak stage embryos (E7.5), Tcf4 expression was detected in anterior endoderm. E8.5 embryos had Tcf-4 expression in rostral neural plate and in alternating rhombomeres of the hindbrain. By E9.5 and thereafter, expression in the hindbrain disappeared and strong expression was detected in the diencephalon. Strikingly Tcf-4 expression in the forebrain was undetected in Small eye mutant embryos indicating that Pax-6 is required for Tcf-4 expression in the forebrain. In developing limbs, Tcf-4 is readily detected starting at E10.5 and is limited to mesenchymal cells surrounding the areas of chondrification. These data indicate a function for Tcf-4 in neural and limb development, two tissues where Wnt signaling plays an essential role.

The molecular basis of embryonic kidney development.

The development of the mature mammalian kidney begins with the invasion of metanephric mesenchyme by ureteric bud. Mesenchymal cells near the bud become induced and convert to an epithelium which goes on to generate the functional filtering unit of the kidney, the nephron. The collecting duct system is elaborated by the branching ureter, the growth of which is dependent upon signals from the metanephric mesenchyme. The process of reciprocal induction between ureter and mesenchyme is repeated many times over during development and is the key step in generating the overall architecture of the kidney. Genetic studies in mice have allowed researchers to begin to unravel the molecular signals that govern these early events. These experiments have revealed that a number of essential gene products are required for distinct steps in kidney organogenesis. Here we review and summarize the developmental role played by some of these molecules, especially certain transcription factors and growth factors and their receptors. Although the factors involved are far from completely known a rough framework of a molecular cascade which governs embryonic kidney development is beginning to emerge.

Comparative analysis of Pax-2 protein distributions during neurulation in mice and zebrafish.

Members of different vertebrate species share a number of developmental mechanisms and control genes, suggesting that they have similar genetic programs of development. We compared the expression patterns of the Pax-2 protein in Mus musculus and Brachydanio rerio to gain a better understanding of the evolution of developmental control genes. We found that the tissue specificity and the time course of Pax-2 expression relative to specific developmental processes are remarkably similar during the early development of the two organisms. The brain, the optic stalk, the auditory vesicle, the pronephros, and single cells in the spinal cord and the hindbrain express Pax-2 in both species. The Pax-2 expression domain in the prospective brain of E8 mouse embryos has not been described previously. Expression appears first during early neurulation at the junction between the midbrain and hindbrain. However, there are some differences in Pax-2 expression between the two species. Most notable, expression at the midbrain/hindbrain boundary is no longer detectable after E11 in the mouse. Using monoclonal antibodies, we could exclude that primary neurons express Pax-2 in the zebrafish spinal cord. Our results confirm that Pax genes are highly conserved both in sequences and in expression patterns, indicating that they may have a function during early development that has been conserved during vertebrate evolution.

Pax2/5 and Pax6 subdivide the early neural tube into three domains.

The nested expression patterns of the paired-box containing transcription factors Pax2/5 and Pax6 demarcate the midbrain and forebrain primordium at the neural plate stage. We demonstrate that, in Pax2/5 deficient mice, the mesencephalon/metencephalon primordium is completely missing, resulting in a fusion of the forebrain to the hindbrain. Morphologically, in the alar plate the deletion is characterized by the substitution of the tectum (dorsal midbrain) and cerebellum (dorsal metencephalon) by the caudal diencephalon and in the basal plate by the replacement of the midbrain tegmentum by the ventral metencephalon (pons). Molecularly, the loss of the tectum is demonstrated by an expanded expression of Pax6, (the molecular determinant of posterior commissure), and a rostral shift of the territory of expression of Gbx2 and Otp (markers for the pons), towards the caudal diencephalon. Our results suggest that an intact territory of expression of Pax2/5 in the neural plate, nested between the rostral and caudal territories of expression of Pax6, is necessary for defining the midbrain vesicle.

Pax2 in development and renal disease.

Pax genes are associated with a variety of developmental mutations in mouse and man that are gene dosage sensitive, or haploinsufficient. The Pax2 gene encodes a DNA binding, transcription factor whose expression is essential for the development of the renal epithelium. Both gain and loss of function mutants in the mouse demonstrate a requirement for Pax2 in the conversion of metanephric mesenchymal precursor cells to the fully differentiated tubular epithelium of the nephron. However, Pax2 expression is down-regulated as cells leave the mitotic cycle. Humans carrying a single Pax2 mutant allele exhibit renal hypoplasia, vesicoureteric reflux, and optic nerve colobomas. Conversely, persistent expression of Pax2 has been demonstrated in a variety of cystic and dysplastic renal diseases and correlates with continued proliferation of renal epithelial cells. Thus, Pax2 misexpresssion may be a key determinant in the initiation and progression of renal diseases marked by increased or deregulated cell proliferation.

Transcription factors in renal development: the WT1 and Pax-2 story.

The development of a complex, multicellular organ, such as the kidney, from two embryonic progenitor tissues requires the activation and suppression of transcription factors that regulate tissue and cell type-specific gene expression. From areas as diverse as fruit fly development and human cancer genetics, a number of important genes have been identified that help to orchestrate the early events of renal epithelium induction and differentiation. The Wilms' tumor-suppressor gene WT1 is critical for regulating the early response of the kidney mesenchyme to induction and may play multiple roles during the course of renal epithelial cell development and tumor formation. The Pax-2 gene is activated in the mesenchyme after induction and is necessary for condensation and perhaps proliferation of the induced cells. How these two important gene products exert their effects will be discussed in light of recent evidence on DNA binding, transcription repression, and protein interactions.

Perceived risks to independent living: the views of older, community-dwelling adults.

The purpose of the present study was to gather the perceptions of older, community-dwelling adults about factors they considered essential for them to remain living within the community. In-depth interviews were conducted with 103 men and women over the age of 65 years who were living in their own home or apartment, within an urban center. Factors such as finances, health, family support, a sense of identity, and a feeling of independence were perceived by older adults to contribute to their ability to remain living in the community. Importantly, older adults viewed threats to this continued independent living as both (a) factors connected to losses and maintenance of capability, but also (b) as impediments to further growth of their personal well-being.

Kidney development branches out.

For more than 40 years now, the developing kidney has served as a model paradigm for epithelial-mesenchymal interactions. The principles of inductive signaling, epithelial cell differentiation, and pattern formation are now being addressed with modern genetic and biochemical tools. In addition to the mammalian kidney organ culture model, both zebrafish and Xenopus laevis demonstrate great potential for investigating the molecular mechanisms of kidney organogenesis within a whole organism. In this review, the papers presented in this special issue are discussed with respect to recent progress in the renal development field. Coincidentally, it has become increasingly clear that progress made in renal development can impact our understanding of the genetic basis of disease.