GUDMAP 1 Projects
Kidney disease is one of the leading health-care costs. Despite the vital importance of the kidney to maintaining the normal physiological equilibrium of an individual, there is a relatively poor understanding of the developmental program that creates the functional organ. Our goal is to generate a detailed spatial map of the cellular expression of selected regulatory genes during mammalian (mouse) kidney development to generate a "molecular anatomy" of the developing kidney. We will also create a series of transgenic mouse strains that will allow the ready identification and genetic manipulation of key cell types. Our aims:
- We will perform a genome-wide analysis of the expression of all genes encoding mouse transcriptional regulators, ligands and cognate surface receptors in the embryonic urogenital system.
- We will generate a high resolution section in situ hybridization (SISH) map of the expression of all genes in Aim 1 in the fetal and neonatal kidney.
- We will perform transcriptional array analysis of renal tubule deficient mouse kidneys and micro-dissected kidney tubules to identify, and subsequently map the expression of tubule specific genes.
- We will use BAC-mediated transgenics to express fluorescent reporter proteins and Cre recombinase in specific cell populations for cell marking, cell fate and genetic manipulation studies... more
The goal of this project is to better define the genetic program that drives kidney formation in the embryo. While all cells carry the same complement of genes, different cell types use, or express, different sets of genes. This is similar to a computer that has a large number of programs, but only executes one or a few programs at a given time. Two computers with the same program capacity could be doing very different things at a given moment. And two cells in the embryo, with the same genes, could be doing very different things because they are using different sets of genes... more
Smooth muscle is critical for the function of many organs that make up the lower urinary tract and reproductive systems. For example, controlled contraction of bladder smooth muscle is needed to empty the bladder at will and rhythmic contractions of uterine smooth muscle are crucial to the delivery of babies. We will follow the development and organization of these and other smooth muscle rich organs in the genitourinary tract using mice that produce fluorescent proteins exclusively in smooth muscle or other cellular compartments of these genitourinary tissues. Our studies will determine what genes are expressed in the cells that make up these organs as they form in the mouse at different times during development. This information will help identify and understand the genes and signals involved in the development and function of these organs... more
The development of genitourinary tract, like any other organ systems, is very complex that requires controlled proliferation and differentiation of various types of cells. To understand the developmental processes that lead to the formation of the GU tract, we need genetic tools that will enable us to monitor gene expression dynamics in vivo, to dissect cell-cell interactions, to trace cell lineages, and to perform biochemical analyses. Our GUDMAP project focuses on generating such tools. We are genetically marking or labeling the different types of cells in the mouse GU tract through knocking fluorescent protein markers and/or the Cre recombinase, or epitope tags, into genes which are specifically expressed in those cell types... more
The overall objective of this proposal is to establish a genome-wide, cell type-specific, computer-based searchable map of gene expression associated with critical periods of development of the normal fetal testis. The fetal testis plays an essential role in normal male urogenital tract development and many male urogenital tract disorders are linked to fetal testis perturbations. To understand the impact of genetic and environmental influences on testicular development, it is essential to determine normal gene expression patterns in the fetal testis during development. The goals of this proposal are to 1) define the 3-dimensional (3-D) spatial gene dynamics in relationship to structural development and hormonal balance in the developing testis and 2) identify cell-specific genes that can be used as biomarkers for key differentiation events. This information will provide researchers with valuable tools for further investigations into normal fetal testicular development as well as the causes, treatment, and prevention of male urogenital tract disorders... more
Congenital anomalies of the urogenital tract (UGT) represent the third most frequent of all birth defects, occurring in approximately 26-30/10,000 live births. Only heart and limb defects are more prevalent. Such defects can vary from severe (persistent cloaca, cystic kidney disease, hydronephrosis, diphallia) to more moderate (hypospadias, streak gonads, horseshoe kidney, micropenis, crytorchidism, unliateral renal agenesis). Some cancers of the urogenital tract (gonadoblastoma, Wilms' tumour) represent a persistence of the embryonic state. In addition, adult onset renal disease and other disorders of the UGT show reactivation of molecules key to the normal development of the UGT. Indeed, there is now evidence that the number of nephrons endowed before birth in your kidneys can affect whether or not you will present with chronic renal disease later in life. All these observations highlight the need to comprehensively understand the molecular basis of UGT development. The starting point for this understanding is the temporal and spatial analysis of all genes expressed during UGT development... more
3D atlas & database of murine urogenital development
The work addresses the challenge of organizing, storing and using gene expression data to facilitate our understanding of genitourinary (GU) development and disease. The work of the database group is being done in close collaboration with laboratories producing this data. We will build a database to collate and disseminate in situ and micro-array gene expression data generated by the GUDMAP Consortium. The GUDMAP gene expression database will be continuously updated, curated, and fully integrated with the GUDMAP atlas. Using histological material provided by the consortium, we will build a morphological atlas that will provide a reference description of GU development in the mouse. The GUDMAP Atlas will function as an integrative spatial, temporal and conceptual framework for a wide range of data relating to GU development and disease. The web-accessible atlas will comprise a time-series (E9 to adult) of 3D digital models of genitourinary development linked to a textual anatomical ontology, and a catalogue of cell types. The GUDMAP Atlas will be linked to the gene expression database, cell catalogue and other relevant resources such that these data can be associated with the appropriate location in the 3D structure of the GU system and the appropriate time during development. Analytical tools, centered on the Atlas, will integrate data at all levels of scale and thus create a bioinformatics environment for the generation of hypotheses about gene function, molecular pathways, the differentiation and behavior of cells and the morphogenesis and growth of tissues. This molecular and morphological description of GU development will thus provide a platform for modeling the processes of development, disease, and therapy... more
Basic developmental neuro-urology studies are needed to gain insight into mechanisms underlying the pathogenesis of neurogenic bladder disorders and innervation deficiencies of external genitalia. Fundamental mechanistic knowledge of how autonomic innervation develops in these structures is lacking. Our long-term goals are to understand the migration processes, neural crest (NC) cell derivatives and essential signaling pathways that contribute to innervation of the developing bladder and external genitalia. We have established a series of transgenic mouse lines that drive expression of histological and fluorescent reporters in NC-derived cells as they migrate into the urogenital tract during development. The aims of this proposal are: 1) to derive a three-dimensional reconstruction of NC derivatives migrating into the developing bladder and genital tubercle based on transgene expression in murine embryos 2) to catalog cell phenotypes of NC derivatives within the bladder and genital tubercle by immunohistochemical labeling of transgene expressing cells with lineage markers and 3) to define the transcriptional profiles of NC-derived cell types in the bladder and genital tubercle during a focused developmental window... more
It is believed that some of the growth mechanisms activated normally during prostate development are reactivated inappropriately during prostate disease. The developing fetal mouse prostate provides an excellent model for elucidating these prostate growth mechanisms. Prostate ductal development is initiated in the fetal male by androgen-dependent growth of epithelial prostatic buds into surrounding urogenital sinus (UGS) mesenchyme. Collaboration between androgen receptors and other less understood signals specifies location, number, and timing of prostatic budding, and later in development facilitates prostate ductal branching morphogenesis and cellular differentiation. The goal of this project is to establish a temporal and spatial atlas of gene expression during key stages of fetal and neonatal mouse prostate development... more
The gonad forms initially as a bipotential primordia that is capable of developing into either a testis or an ovary. Whether a testis or ovary forms is determined by a critical cell fate decision in the early fetal gonad. Disruption of this primary decision is responsible for many of the phenotypes identified in the clinic as disorders of sexual development (DSDs)... more