Tim B. Schedl, Ph.D.

Professor
Genetics

Molecular Genetics and Genomics Program
Developmental, Regenerative and Stem Cell Biology Program

  • 314-362-6162

  • 314-362-6164

  • 8232

  • MRB - McKinley Research Building, Room 5305

  • ts@wustl.edu

  • http://www.genetics.wustl.edu/tslab/

  • germ cells, C. elegans, genetics, development, functional genomics

  • Control of germline stem cells and meiotic development in C. elegans

Research Abstract:

Germ cells are unique in animals as they are the means by which genetic material and cytoplasmic constituents are passed through generations. We are studying two processes that are critical for germ cell development: 1) the decision between the stem cell fate vs. initiate meiotic development and 2) control of progression through meiotic prophase and coordination with oogenesis. Little is know about these processes in any animal. We utilize C. elegans because of its transparency, tractable genetics and functional genomics. Cell-cell signaling regulates the two germline processes. GLP-1/Notch receptor signaling controls the stem cell vs. meiotic initiation choice, while RAS-ERK MAP kinase signaling acts at multiple points to control meiotic prophase cell cycle transitions and oogenesis. We use genetic analysis, including high-throughput RNAi screens in sensitized genetic backgrounds, to identify genes necessary for different steps in germline development and define the regulatory pathways in which they function.

In the Pediatrics clinic, ~2/3 of patients with an inherited birth defect do not receive a molecular diagnosis following whole exome sequencing. This is in part due to potentially pathogenic variants (amino acid changes), but in genes of unknown clinical significance (GUS). We have begun a pilot project, in collaboration with Pediatric geneticists, to use C. elegans to provide experimental support that the GUS, and patient specific variants, contributes to disease presentation. For GUS where there is a C. elegans ortholog, the patient specific variant is knocked in by CRISPR/Cas9 and worms are examined for deleterious phenotypes. Our hope is that the ability to rapidly associate genotype with phenotype in C. elegans can be exploited to expand the number of genes and variants that contribute to human disease.

Selected Publications:

Brenner JL, Schedl, T. (2016). Germline stem cell differentiation entails regional control of cell fate regulator GLD-1 in Caenorhabditis elegans. Genetics, 202:1085-1103 PMCID: PMC4788111

Fox PM, Schedl T. (2015). Analysis of Germline Stem Cell Differentiation Following Loss of GLP-1 Notch Activity in Caenorhabditis elegans. Genetics. 201:167-84. PMCID: PMC4566261

Hou X, Zhang L, Han L, Ge J, Ma R, Zhang X, Moley K, Schedl T, Wang Q. (2015). Differing roles of pyruvate dehydrogenase kinases during mouse oocyte maturation. J Cell Sci. 128:2319-29. PMCID: PMC4510846.

Arur S, Schedl T. (2014). Generation and purification of highly specific antibodies for detecting post-translationally modified proteins in vivo. Nat Protoc. 9:375-95. PMCID: PMC4124490

Hansen D, Schedl T. (2013). Stem cell proliferation versus meiotic fate decision in Caenorhabditis elegans. Adv Exp Med Biol. 757:71-99. PubMed PMID: 22872475; PubMed Central PMCID: PMC3786863.

Luzzo KM, Wang Q, Purcell SH, Chi M, Jimenez PT, Grindler N, Schedl T, Moley KH. (2012). High fat diet induced developmental defects in the mouse: oocyte meiotic aneuploidy and fetal growth retardation/brain defects. PLoS One. 7:e49217. PMCID: PMC3495769.

Fox PM, Vought VE, Hanazawa M, Lee MH, Maine EM, Schedl T. (2011). Cyclin E and CDK-2 regulate proliferative cell fate and cell cycle progression in the C. elegans germline. Development. 138:2223-34. PMCID: PMC3091494.

Green RA, Kao HL, Audhya A, Arur S, et al. (2011). A high-resolution C. elegans essential gene network based on phenotypic profiling of a complex tissue. Cell. 2011 Apr 29;145(3):470-82. PMCID: PMC3086541

Arur S, Ohmachi M, Berkseth M, Nayak S, Hansen D, Zarkower D, Schedl T. (2011). MPK-1 ERK controls membrane organization in C. elegans oogenesis via a sex-determination module. Dev Cell. 20:677-88. PMCID: PMC3098718

Arur S, Ohmachi M, Nayak S, Hayes M, Miranda A, Hay A, Golden A, Schedl T. (2009). Multiple ERK substrates execute single biological processes in Caenorhabditis elegans germ-line development. Proc Natl Acad Sci U S A. 106:4776-81. PMCID: PMC2660749.

Last Updated: 8/14/2017 9:37:38 AM

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