Postdoctoral Position Available

Mark Alkema, Ph.D.

Academic Role: Assistant Professor

Faculty Appointment(s) In:
   Neurobiology

Other Affiliation(s):
   Program in Neuroscience

C. elegans Behavioral Genetics

Our focus is to understand the molecular and cellular basis of behavioral plasticity. We are studying how the environment modulates behavior of the nematode Caenorhabditis elegans. The C. elegans nervous system is very simple and extraordinarily well described. The detailed knowledge  of the C. elegans nervous system combined with its amenability to genetic analysis and laser microsurgery allows us to define neural circuits that control behavior and study behavior at the molecular and cellular level.

C. elegans drastically changes it’s behavior in response to food: in ample food, pharyngeal pumping (feeding) and egg laying are stimulated, whereas locomotion is inhibited. In the absence of food, pharyngeal pumping and egg laying are inhibited and locomotion is stimulated. We are examining the role of the biogenic amines, serotonin and octopamine, in the modulation of these food dependent behaviors. Through the analysis of octopamine deficient mutants we found that octopamine stimulates locomotion and inhibits pharyngeal pumping and egg laying in the absence of food and directly antagonizes the role of serotonin in these behaviors. We are characterizing C. elegans octopamine and serotonin receptors to define how octopaminergic and serotonergic neural circuits interface and control food dependent behaviors.

We also found that tyramine, the biosynthetic precursor of octopamine, has a role independent of octopamine in C. elegans behavior. The analysis of tyramine-deficient animals showed that tyramine is required for the inhibition of head movements in response to gentle touch with an eye lash  (Fig. 1) Forward locomotion of wild-type animals is accompanied by oscillatory head movements. Anterior touch of wild-type animals with an eyelash induces backing during which head oscillations are suppressed. Tyramine deficient mutants fail to suppress head oscillations during backing. Using laser microsurgery we defined a neural circuit that regulates the suppression of head oscillations in response to the stimulation of mechanosensory neurons (Fig. 2) We identified several mutants that, like the tyramine deficient mutants, fail to suppress head oscillations in response to anterior touch. The characterization of these mutants should allow us to identify new tyraminergic signaling components.

The repeated action of biogenic amines can cause long-term changes in synaptic function. Studies in Aplysia, Drosophila and mice have found an important role for the cyclic AMP-response binding protein, CREB in long-term memory formation. To explore the role of C. elegans CREB crh-1 we isolated crh-1 mutant animals. We found that crh-1 mutants have behavioral and developmental defects consistent with the hypothesis that crh-1 functions downstream of serotonin to mediate behavioral and developmental changes that depend on long-term assessment of food availability.

Ultimately, we hope that our studies will teach us more about the basic principles that underlie behavioral plasticity of more complex neural systems.

Forward locomotion of wild-type animals is accompanied by oscillatory head movements. Anterior touch of wild-type animals with an eyelash induces backing during which head oscillations are suppressed. Tyramine deficient  mutants fail to suppress head oscillations during backing.

Model for the neural circuit that regulates the suppression of head oscillations in response to anterior touch. Tactile stimulation of the anterior touch sensory neurons (ALM/AVM) leads to the activation of the backward locomotion command neurons (AVD/AVA). The tyraminergic RIM neurons are activated through gap junctions by the AVA neurons, leading to the release of tyramine and the inhibition of the cholinergic head motor neurons, of head muscle contractions, and consequently of head oscillations.

Representative Publications

Alkema MJ, Hunter-Ensor M, Ringstad N, Horvitz HR (2005)  Tyramine functions independently of octopamine in the Caenorhabditis elegans nervous system. Neuron 46: 247-260.

Akasaka T, van Lohuizen M, van der Lugt N, Mizutani-Koseki Y, Kanno M, Taniguchi M, Vidal M, Alkema M, Berns A, Koseki H.  Mice doubly deficient for the Polycomb Group genes Mel18 and Bmi1 reveal synergy and requirement for maintenance but not initiation of Hox gene expression. Development. 2001 May;128(9):1587-97.

Bel S, Core N, Djabali M, Kieboom K, Van der Lugt N, Alkema MJ, Van Lohuizen M.            Genetic interactions and dosage effects of Polycomb group genes in mice. Development. 1998 Sep;125(18):3543-51.

Alkema MJ, Jacobs J, Voncken JW, Jenkins NA, Copeland NG, Satijn DP, Otte AP, Berns A, van Lohuizen M.  MPc2, a new murine homolog of the Drosophila polycomb protein is a member of the mouse polycomb transcriptional repressor complex.  J Mol Biol. 1997 Nov 14;273(5):993-1003.

Alkema MJ, Jacobs H, van Lohuizen M, Berns A.  Pertubation of B and T cell development and predisposition to lymphomagenesis in Emu Bmi1 transgenic mice require the Bmi1 RING finger. Oncogene. 1997 Aug 18;15(8):899-910.

Satijn DP, Gunster MJ, van der Vlag J, Hamer KM, Schul W, Alkema MJ, Saurin AJ, Freemont PS, van Driel R, Otte AP.  RING1 is associated with the polycomb group protein complex and acts as a transcriptional repressor.  Mol Cell Biol. 1997 Jul;17(7):4105-13.

Gunster MJ, Satijn DP, Hamer KM, den Blaauwen JL, de Bruijn D, Alkema MJ, van Lohuizen M, van Driel R, Otte AP. Identification and characterization of interactions between the vertebrate polycomb-group protein BMI1 and human homologs of polyhomeotic.  Mol Cell Biol. 1997 Apr;17(4):2326-35.

Alkema MJ, Bronk M, Verhoeven E, Otte A, van 't Veer LJ, Berns A, van Lohuizen M.           Identification of Bmi1-interacting proteins as constituents of a multimeric mammalian polycomb complex.  Genes Dev. 1997 Jan 15;11(2):226-40.

van der Lugt NM, Alkema M, Berns A, Deschamps J.  The Polycomb-group homolog Bmi-1 is a regulator of murine Hox gene expression.  Mech Dev. 1996 Aug;58(1-2):153-64.

Alkema MJ, van der Lugt NM, Bobeldijk RC, Berns A, van Lohuizen M.  Transformation of axial skeleton due to overexpression of bmi-1 in transgenic mice.  Nature. 1995 Apr 20;374(6524):724-7.

Berns A, van der Lugt N, Alkema M, van Lohuizen M, Domen J, Acton D, Allen J, Laird PW, Jonkers J.  Mouse model systems to study multistep tumorigenesis. Cold Spring Harb Symp Quant Biol. 1994;59:435-47.

Alkema MJ, Wiegant J, Raap AK, Berns A, van Lohuizen M.  Characterization and chromosomal localization of the human proto-oncogene BMI-1.  Hum Mol Genet. 1993 Oct;2(10):1597-603.

Winter AJ, Alkema MJ, Groot Koerkamp MJ, van der Horst G, Mul Y, Tabak HF.  Interlocked circle formation by group I introns: structural requirements and mechanism.  Nucleic Acids Res. 1993 Jul 11;21(14):3217-26.

Verrijzer CP, Alkema MJ, van Weperen WW, Van Leeuwen HC, Strating MJ, van der Vliet PC.  The DNA binding specificity of the bipartite POU domain and its subdomains.  EMBO J. 1992 Dec;11(13):4993-5003.

Biography

Mark Alkema received his B. Sc. (1990) from the Department at the University of Amsterdam and Ph.D. (1996) from the University of Amsterdam, The Netherlands. He received a Human Frontiers Science Program fellowship and a Merck / M.I.T. Fellowship to do postdoctoral work at the Massachusetts Institute of Technology in the laboratory of Bob Horvitz. He joined the Department of Neurobiology at the University of Massachusetts Medical School as a faculty member in June, 2005.

Office: 717
Phone: 508-856-6158
E-mail: Mark.Alkema@umassmed.edu
Keywords: Neurobiology, Organisms - C. elegans, Learning and Memory, Neuromodulation , Genetics

More on Mark Alkema's Research Research | Figures | Publications | Biography View All Sections on One Page

Postdoctoral Position Available A postdoctoral position is available to study in this laboratory. Contact Dr. Mark Alkema for additional details.