Mathies Homepage

Organs are generated from precursor cells that have the potential to generate all tissues of the adult organ. In the course of their development, these precursor cells divide to generate cells that are increasingly restricted in their developmental potential until they finally differentiate into the mature tissues of the organ. How are cells specified to form a particular organ? How do they generate the proper array of differentiated cell types? How is this process coordinated in space and time? We aim to define the gene regulatory network (GRN) that controls development of the reproductive organs in C. elegans. This will expand the existing repertoire of defined GRNs and will allow us to learn general principles of the regulatory logic of organ formation.

The adult reproductive organs develop from a primordium that contains four precursor cells – two somatic gonadal precursors (SGPs) and two germ line precursors (PGCs). The primordium forms late in embryogenesis when the two SGPs migrate toward and surround the PGCs. The primordium remains like this until the embryo hatches into an L1 larva. At this stage, the SGPs are poised to make several key cell fate decisions. First, they divide to produce daughter cells with different developmental potential: one will produce a distal tip cell (DTC), while the other will produce an anchor cell (AC). Second, they position these cells relative to the proximal-distal axis of the organ. Third, they produce different cell types in the two sexes. For example, males have a linker cell (LC) while hermaphrodites have an anchor cell. These cell fate decisions can be easily monitored using molecular markers for several cell types (e.g. DTCs, ACs, and LCs). With the powerful genetic and genomic resources available in C. elegans, this simple organ provides an outstanding system for defining the genetic networks controlling organogenesis.

AC-DTC

The SGPs divide to generate daughter cells with different fates. Inner daughters give rise to the anchor cell (AC), while outer daughters give rise to distal tip cells (DTC).

Defining the early gonadogenesis network. Genetic studies have identified several transcriptional regulators that control early aspects of SGP development. These genes act together to control key cell fate decisions, and they are part of a larger gene regulatory network that guides the SGPs along their developmental path. There are still many missing nodes in the network. For example, we do not know what gene(s) specify the SGP fate. To identify new genes in the network, we are using a combination of classical and molecular genetics. Our long-term goal is to describe the complete genetic network controlling SGP development.

Current projects:
1) ehn-3: an SGP-specific regulator. The ehn-3 gene encodes related zinc finger proteins that are expressed specifically in the SGPs and control several processes in early SGP development. The EHN-3 proteins have sequence and structural similarity to the Ikaros family of transcriptional regulators. Ikaros is important for development of hematopoietic progenitors into differentiated lymphocytes, much like ehn-3 is required for development of SGPs into differentiated cell types. We are using a combination of DNA binding studies and genetic enhancer screens to learn how ehn-3 controls diverse aspects of SGP development.

2) Regulome RNAi screen. The "regulome" includes all genes that are likely to be involved in gene regulation (transcription factors, cell-cell signaling components, and chromatin regulators). We recently completed an RNAi screen of this set of genes and found many new regulators of SGP development. We are currently incorporating these genes into the gene regulatory network.

Evolution of gene regulatory networks. How do complex GRNs evolve? We are beginning to explore this question using two related nematode species, C. elegans and C. briggsae. These nematodes diverged ~80-100 million years ago. Many of the tools available to C. elegans researchers are also available in C. briggsae. The early stages of somatic gonad development are indistinguishable in these two nematodes, yet some of the genes in the C. elegans GRN appear to be absent from the C. briggsae genome. Through comparative studies in C. elegans and C. briggsae, we hope to learn how complex gene regulatory networks change over the course of evolution.

Welchman, D.P., Mathies, L.D. and Ahringer, J. (2007). Similar requirements for CDC-42 and the PAR-3/PAR-6/PKC-3 complex in diverse cell types. Dev. Biol. 305(1): 347–357.Download a PDF file

Mathies, L.D., Schvarzstein, M., Morphy, K.M., Blelloch, R., Spence, A.M., and Kimble, J. (2004). TRA1/GLI controls development of somatic gonadal precursors in C. elegans. Development 131: 4333-4343. Download a PDF file

Chang, W., Tilmann, C., Thoemke, K., Markussen, F.-H., Mathies, L.D., Kimble, J., Zarkower, D. (2004). A forkhead protein controls sexual identity of the C. elegans male somatic gonad. Development 131: 1425-1436. Download a PDF file.

Mathies, L.D., Henderson, S.T. and Kimble, J. (2003). The C. elegans Hand gene controls embryogenesis and early gonadogenesis. Development 130: 2881-2892. Download a PDF file.

Belfiore, M., Mathies, L.D., Pugnale, P., Moulder, G., Barstead, R., Kimble, J. and Puoti, A. (2002). The MEP-1 Zn-finger protein acts with MOG DEAH-box proteins to control gene expression via the fem-3 3'-UTR in C. elegans. RNA. 8: 725-739.

Manak, J.R., Mathies, L.D., Scott, M.P. (1994). Regulation of a decapentaplegic midgut enhancer by homeotic proteins. Development 120: 3605-3619.

Mathies, L.D., Kerridge, S., Scott, M.P. (1994). Role of the teashirt gene in Drosophila midgut morphogenesis: secreted proteins mediate the action of homeotic genes. Development 120: 2799-2809.

Zeng, W., Andrew, D.J., Mathies, L.D., Horner, M.A., Scott, M.P. (1993). Ectopic expression and function of the Antp and Scr homeotic genes: the N terminus of the homeodomain is critical to functional specificity. Development 118: 339-352.

Laura D. Mathies

Assistant Professor of Genetics

Genetic Regulatory Networks Controlling Organogenesis