Proper formation of the kidney into a fully functional organ requires the integration of multiple signaling events. During the reiterative process of kidney tubule induction, a delicate balance is struck between signals that maintain a progenitor cell population and those that lead to differentiation. A tip in the balance toward either side has catastrophic consequences. A failure to convert progenitor cells into differentiated epithelia can result in either hypoplasia or progenitor cell-derived cancers, such as Wilms'tumors. Alternatively, if the proper number of progenitor cells is not maintained, they will be depleted prematurely, preventing further nephrogenesis and once again resulting in hypoplasia. Currently, we know little about the molecular mechanisms that control the balance between progenitors and differentiated tubular cells during tissue homeostasis or how these signals are regulated during normal development of the kidney. One of the central dogmas in kidney progenitor cell biology has been that canonical Wnt signaling must be repressed in the progenitor cells in order to keep them undifferentiated. However, we have recently discovered that not only is the canonical Wnt signaling pathway active in progenitors, it may in fact have higher levels of activity in this cell type than in the rest of the metanephric mesenchyme. Specifically, we have found that Wnt9b activates expression of a distinct set of target genes specifically within the progenitor cells and that this occurs through a b-catenin dependent mechanism. We hypothesize that high levels of canonical Wnt signaling activity in progenitor cells are promoted by the canonical Wnt agonists, R-spondin1 and 3, and that the expression of these genes in progenitor cells is dependent on the activity of the transcription factor Six2. However, several questions still remain: Why do some kidney mesenchymal cells differentiate into tubules, while others are maintained in a progenitor pool? What molecules regulate the choice between these alternative cellular states? Does Wnt9b signaling play a role in both populations? And which effectors modulate their different responses? The experiments outlined in this proposal are designed to test our hypotheses, as well as to enhance our understanding of the factors that regulate Wnt9b signaling and progenitor cell biology.
Unlike some organs, such as the pancreas, the functional unit of the kidney is not a single cell but instead a collection of cells organized into a tubule. The future of bioengineering tissue for organ replacement, at least for the kidney and other similar organs like the lung, thus relies not only on our ability to identify precursor or """"""""stem"""""""" cells but also in our ability to convert these cells in functional tubules. We are interested in understanding the molecular and cellular processes that are required to convert individual cells into tubules.
| Ramalingam, Harini; Fessler, Alicia R; Das, Amrita et al. (2018) Disparate levels of beta-catenin activity determine nephron progenitor cell fate. Dev Biol 440:13-21 |
| Mathew, Sijo; Palamuttam, Riya J; Mernaugh, Glenda et al. (2017) Talin regulates integrin ?1-dependent and -independent cell functions in ureteric bud development. Development 144:4148-4158 |
| Pan, Xinchao; Karner, Courtney M; Carroll, Thomas J (2017) Myc cooperates with ?-catenin to drive gene expression in nephron progenitor cells. Development 144:4173-4182 |
| Schnell, Ulrike; Carroll, Thomas J (2016) Planar cell polarity of the kidney. Exp Cell Res 343:258-266 |
| Elias, Bertha C; Das, Amrita; Parekh, Diptiben V et al. (2015) Cdc42 regulates epithelial cell polarity and cytoskeletal function during kidney tubule development. J Cell Sci 128:4293-305 |
| Li, Yuwen; Liu, Jiao; Li, Wencheng et al. (2015) p53 Enables metabolic fitness and self-renewal of nephron progenitor cells. Development 142:1228-41 |
| Caprioli, Arianna; Villasenor, Alethia; Wylie, Lyndsay A et al. (2015) Wnt4 is essential to normal mammalian lung development. Dev Biol 406:222-34 |
| Pan, Xinchao; Schnell, Ulrike; Karner, Courtney M et al. (2015) A Cre-inducible fluorescent reporter for observing apical membrane dynamics. Genesis 53:285-93 |
| Wang, Shan-Shan; Gu, Yi-Feng; Wolff, Nicholas et al. (2014) Bap1 is essential for kidney function and cooperates with Vhl in renal tumorigenesis. Proc Natl Acad Sci U S A 111:16538-43 |
| Murphy, Andrew J; Pierce, Janene; de Caestecker, Christian et al. (2014) Aberrant activation, nuclear localization, and phosphorylation of Yes-associated protein-1 in the embryonic kidney and Wilms tumor. Pediatr Blood Cancer 61:198-205 |
Showing the most recent 10 out of 22 publications
