We focus on genes and regulatory pathways that are involved in the informational exchange of the organism with its environment. This includes the (neural) response of C. elegans to sensory stimulation (mechanical, thermal), to bacterial infection, and to consequences of food deprivation. The overwhelming majority of genes we study are conserved in evolution. C. elegans in vivo models help us to understand the functions of the corresponding human factors and their dysfunction in disease. The functional analyses of human candidate disease genes are facilitated by the excellent and fast methods available to generate transgenic animals, the short time-frame in which genetic experiments can be accomplished (transgenic lines can be obtained in 1-2 weeks), and the opportunity to determine and manipulate expression patterns of candidate genes on the level of single cells, whose functions are mostly known.

Alzheimer's disease
The presenilins - an evolutionary conserved family of proteins associated with neurogenesis, myogenesis and Alzheimer's Disease. Mutations in the human presenilins PS1 and PS2 are the major cause of hereditary cases of Alzheimer's Disease with an early onset (currently, the youngest known patient is only 16 years old!). Presenilins are part of the large, membrane-associated gamma-secretase complex that cleaves the Amyloid Precursor Protein (APP) and the Notch receptor of intercellular signalling. The C. elegans presenilins sel-12 and hop-1 are facilitating signaling by LIN-12 and GLP-1, the two C. elegans Notch proteins. Mutations in hop-1 do not have an obvious phenotype (like the mouse PS2), whereas mutations in sel-12 cause multiple defects in nerve cell growth, muscle attachment and cell specifications. As one consequence, sel-12 mutant animals are egg-laying defective. We want to understand the role of presenilins in myogenesis, neurogenesis and Alzheimer's Disease. We have established C. elegans models that allow us to test human presenilin variants and to identify presenilin modifiers. Modifiers are mutants of additional genes that can fully suppress the presenilin mutant defects. Currently, we work on several of these modifier genes to characterize their role and to identify targets for pharmacological intervention.

Presenilin function in Caenorhabditis elegans.
Smialowska A, Baumeister R
Neurodegener Dis. 2006;3(4-5):227-32
PMID: 17047361 [PubMed - indexed for MEDLINE]

The GxGD motif of presenilin contributes to catalytic function and substrate identification of gamma-secretase.
Yamasaki A, Eimer S, Okochi M, Smialowska A, Kaether C, Baumeister R, Haass C, Steiner H
J Neurosci. 2006 Apr 5;26(14):3821-8
PMID: 16597736 [PubMed - indexed for MEDLINE]

Parkinson's disease
Parkinson's Disease is characterized by the progressive degradation of the dopaminergic nervous system. The study of hereditary cases of the disease have greatly advanced our understanding of the molecular background of disease mechanism. Mutations in the human Parkin gene result in a very aggressive, juvenile, recessive form of Parkinson's Disease. The parkin gene is considered to encode a ubiquitin ligase expressed in dopaminergic neurons and other nerve cells, with yet poorly defined substrates. It is currently not understood why parkin gene knock-outs in several model organisms do not result in an obvious phenotype. The nervous system of the nematode C. elegans consists of only eight dopaminergic neurons that can be visualized with GFP markers in the living animal. Previous experiments have shown that the C. elegans dopaminergic neurons are susceptible to MPTP toxicity, a neurotoxin that is known to kill dopaminergic neurons in humans and rats. Therefore, the nematode is an interesting alternative to vertebrate models in order to study the hallmarks of Parkinson's Disease.

Caenorhabditis elegans as a model system for Parkinson's disease.
Schmidt E, Seifert M, Baumeister R
Neurodegener Dis. 2007;4(2-3):199-217
PMID: 17596715 [PubMed - indexed for MEDLINE]

A Caenorhabditis elegans Parkin mutant with altered solubility couples alpha-synuclein aggregation to proteotoxic stress.
Springer W, Hoppe T, Schmidt E, Baumeister R
Hum Mol Genet. 2005 Nov 15;14(22):3407-23
PMID: 16204351 [PubMed - indexed for MEDLINE]

Insulin signaling, stress response, and aging
The DAF-2 insulin receptor-like signaling pathway controls metabolism, development, longevity, and stress response in C. elegans. Here we show that SGK-1, the C. elegans homologue of the serum- and glucocorticoid- inducible kinase SGK, acts in parallel to the AKT kinases to mediate DAF-2 signaling. Loss of sgk-1 results in defective egg-laying, extended generation time, increased stress resistance, and an extension of life span. SGK-1 forms a protein complex with the AKT kinases, and is activated by and strictly depends on PDK-1. We show that the AKT-1/AKT-2/SGK-1 complex contributes to the direct phosphorylation and inactivation of DAF-16/FKHRL1. Thereby, AKT-1/AKT-2/SGK-1 competes with a parallel branch within the DAF-2 pathway. Remarkably, SGK-1, but not AKT-1 or AKT-2, is the crucial factor in this kinase complex to control development, stress response and longevity. The high degree of evolutionary conservation of protein sequences and phosphorylation sites suggests a similar regulatory complex in mammalian insulin signaling.

C. elegans SGK-1 is the critical component in the Akt/PKB kinase complex to control stress response and life span.
Hertweck M, Göbel C, Baumeister R
Dev Cell. 2004 Apr;6(4):577-88
PMID: 15068796 [PubMed - indexed for MEDLINE]

Duchenne Muscular Dystrophy
Duchenne muscular dystrophy (DMD) is one of the most severe X-linked, inherited diseases of childhood, characterized by progressive muscle wasting and weakness as the consequence of mutations in the dystrophin gene. The protein encoded by dystrophin is a huge cytosolic protein that links the intracellular F-actin filaments to the members of the dystrophin-glycoprotein-complex (DGC). Dystrophin deficiency results in the absence or reduction of complex components that are degraded through an unknown pathway. We show here that muscle degeneration in a Caenorhabditis elegans DMD model is efficiently reduced by downregulation of chn-1, encoding the homologue of the human E3/E4 ubiquitylation enzyme CHIP. A deletion mutant of chn-1 delays the cell death of body-wall muscle cells and improves the motility of animals carrying mutations in dystrophin and MyoD. Elimination of chn-1 function in the musculature, but not in the nervous system, is sufficient for this effect, and can be phenocopied by proteasome inhibitor treatment. This suggests a critical role of CHIP/CHN-1-mediated ubiquitylation in the control of muscle wasting and degeneration and identifies a potential new drug target for the treatment of this disease.

A mutation in CHN-1/CHIP suppresses muscle degeneration in Caenorhabditis elegans.
Nyamsuren O, Faggionato D, Loch W, Schulze E, Baumeister R
Dev Biol. 2007 Dec 1;312(1):193-202
PMID: 17961535 [PubMed - indexed for MEDLINE]

Regulation of the myosin-directed chaperone UNC-45 by a novel E3/E4-multiubiquitylation complex in C. elegans.
Hoppe T, Cassata G, Barral JM, Springer W, Hutagalung AH, Epstein HF, Baumeister R
Cell. 2004 Aug 6;118(3):337-49
PMID: 15294159 [PubMed - indexed for MEDLINE]

A C. elegans pain model
C. elegans, like most other organisms, responds to noxious (potentially damaging) mechanical, and, as we have shown, thermal stimuli by a withdrawal reflex. The cellular and molecular basis of mechanosensation (touch response) have first been addressed by Martin Chalfie's (Columbia University, New York) groundbreaking work. In contrast, we only begin to understand the molecular details of thermal perception.

Recently, we have shown that C. elegans thermal perception can be modulated pharmacologically, most notably by peripherally acting pain medication. This suggests that we can identify genes which, when mutated, alter the drug response. We currently identify the genetic pathways that contribute to the perception of noxious heat. In addition, using laser microsurgery, we locate the sensory neurons that are involved in the perception of temperature. Recently, we cloned the first gene whose mutations reduce heat perception.

Thermal avoidance in Caenorhabditis elegans: an approach to the study of nociception.
Wittenburg N, Baumeister R
Proc Natl Acad Sci U S A. 1999 Aug 31;96(18):10477-82
PMID: 10468634 [PubMed - indexed for MEDLINE]

UNC-86/Brn-3b/POU4f3: A transcription factor required for mechanoreceptor differentiation, function, and survival
The POU transcription factor UNC-86 and its vertebrate homologs are essential for the differentiation of mechanosensors. In C. elegans, the unc-86 gene is expressed in 57 neurons, and specifies all six mechanoreceptors that sense body touch. In mouse and humans, the vertebrate orthologues of unc-86 are expressed in the inner and outer hair cells of the Organ of Corti (inner ear). Their functional loss results in progressive hearing loss at age 20-50. We have established in vivo (C. elegans, yeast) and in vitro models to study the DNA and protein interaction properties of UNC-86. Currently, we examine how a ternary complex of UNC-86, specific DNA binding sites and various protein interactors work together to control the expression of downstream effector genes.

Protein interaction surface of the POU transcription factor UNC-86 selectively used in touch neurons.
Röhrig S, Röckelein I, Donhauser R, Baumeister R
EMBO J. 2000 Jul 17;19(14):3694-703
PMID: 10899123 [PubMed - indexed for MEDLINE]

Identification of amino acid residues in the Caenorhabditis elegans POU protein UNC-86 that mediate UNC-86-MEC-3-DNA ternary complex formation.
Röckelein I, Röhrig S, Donhauser R, Eimer S, Baumeister R
Mol Cell Biol. 2000 Jul;20(13):4806-13
PMID: 10848606 [PubMed - indexed for MEDLINE]

Bacterial infection, Biofilm formation
During the establishment of a bacterial infection, the surface molecules of the host organism are of particular importance since they mediate the first contact with the pathogen. In Caenorhabditis elegans, mutations in the srf-3 locus confer resistance to infection by Microbacterium nematophilum, and also prevent biofilm formation by Yersinia pseudotuberculosis, a close relative of the bubonic plague agent Yersinia pestis. We cloned srf-3 and show that it encodes a multitransmembrane hydrophobic protein resembling nucleotide sugar transporters of the Golgi apparatus membrane. srf-3 is exclusively expressed in secretory cells, consistent with its proposed function in cuticle/surface modification. We demonstrate that SRF-3 can function as a nucleotide sugar transporter in heterologous in vitro and in vivo systems. UDP-galactose and UDP-N-acetylglucosamine are substrates for SRF-3. We propose that the inability of Yersinia biofilms and M. nematophilum to adhere to the nematode cuticle is due to an altered glycoconjugate surface composition of the srf-3 mutant.

Loss of srf-3-encoded nucleotide sugar transporter activity in Caenorhabditis elegans alters surface antigenicity and prevents bacterial adherence.
Höflich J, Berninsone P, Göbel C, Gravato-Nobre MJ, Libby BJ, Darby C, Politz SM, Hodgkin J, Hirschberg CB, Baumeister R
J Biol Chem. 2004 Jul 16;279(29):30440-8
PMID: 15123614 [PubMed - indexed for MEDLINE]