Mit department of biology: h. robert horvitz

MIT Department of Biology: H. Robert Horvitz
Home Faculty and Areas of Research H. Robert Horvitz OVERVIEW
Medical InstitutePh.D. 1974, Harvard University transduction, cell lineage, cell fate, and morphogenesis, with some emphasis on nervous system development. Study ofthe cellular and molecular mechanisms that controlanimal behavior (particularlylocomotion and egg laying), including the regulation ofmuscle contraction, the function of serotonergic andoctopaminergic neurons, and memory and learning. Human molecular genetics, with focuson the neurodegenerative disease amyotrophic lateralsclerosis.
How does the genome
control animal development
and behavior?
To answer this
question, we isolate and
characterize developmental
and behavioral mutants of C.
. Because the complete
cellular anatomy (including
the complete wiring diagram
of the nervous system) and
MIT Department of Biology: H. Robert Horvitz
the complete cell lineage of C. elegans are known, mutantanimals can be studied at the level of single cells and evensingle synapses. Because the complete DNA sequence of theC. elegans genome is available, genes defined by mutations can be rapidlycloned and analyzed. In addition, genes defined by sequence similarity to knowngenes can be easily identified and mutated. We have studiedmany genes that play specific roles in development andbehavior. Programmed Cell Death
occurring or “programmed”
cell death is widespread
during C. elegans
development. Our studies are
defining a molecular genetic
pathway for programmed cell
death. This pathway is proving
to be conserved amongst
animals, including humans.
For example, the killer gene
ced-3 encodes a caspase
(cysteine aspartate protease);
mammalian caspases similarly
cause programmed cell death.
ced-3 action is facilitated by
ced-4, which is similar to
human Apaf-1, identified
because it promotes
mammalian caspase activation
in vitro. ced-4 function is
blocked by ced-9, which
protects cells against
programmed cell death and is
similar to the human
proto-oncogene bcl-2, which
also protects against cell
MIT Department of Biology: H. Robert Horvitz
death. ced-9 activity is inhibited by the worm killer gene egl-1, which is similar to a number of mammalian killergenes. The activity of egl-1 is controlled in a cell-specific fashion by other genes that specify which cells are to live and which are to die. Programmed cell death appears to be initiated by the transcriptional activation of egl-1, the protein product of which binds the mitochondrial protein CED-9 and causes the release of CED-4 from CED-9 and the translocation of CED-4from the mitochondrial to the nuclear membrane. The engulfment of a dying cell involves two parallel signal transduction pathways: theABC transporter CED-7 promotes cell-corpse recognition by the CED-1 transmembrane receptor, while the CED-2 Crk protein and the CED-10 Rac GTPase promote cytoskeletal reorganization and cell shape changes by the engulfing cell.
The engulfment process not only removes dying cells but also actively causes cells to die.
Signal Transduction: Cell
signaling plays an important
role in C. elegans
development. We are studying
the ways in which cell
signaling regulates cell fate,
cell division, cell migration,
and nerve process outgrowth.
We have focused considerable
attention on the induction of
MIT Department of Biology: H. Robert Horvitz
vulval development in the hermaphrodite by the gonadal anchor cell and have characterized many genes involved in the response to the anchor cell signal. One of these genes, let-60, encodes a Ras protein that functions as aswitch in the pathway of vulval induction. A set of at least 19 genes act like tumor suppressor genes to antagonize the Ras pathway during vulval development. One of these genes, lin-35, encodes a protein similar to the product of the human tumor suppressor gene Rb, and two other genes, dpl-1and efl-1, encode DP and E2F transcription factors, respectively.
Cell Lineage, Cell Fate and
We have
identified numerous genes
that control cell lineage and
cell fate during C. elegans
development. Many of these
genes encode proteins similar
to known transcription factors,
and our studies indicate that
the generation of cell diversity
during development is in part
regulated by a cascade of
interacting transcription
factors. Because two
heterochronic genes, which
control the developmental
timing of cell lineage and cell
fate, encode the founding
members of a novel 21-22 nt
family of regulatory RNAs
found in all animals examined
to date, we have initiated a
genomics/robotics project to
MIT Department of Biology: H. Robert Horvitz
analyze the more than 100 such micro-RNAs encoded by the C. elegans genome.
Morphogenesis: Epithelial
invagination is involved in
many cases of morphogenesis
during animal development.
We are analyzing the
epithelial invagination that
occurs during C. elegans
vulval development. We have
identified eight genes required
for this process and have
determined that these genes
encode proteins involved in
Neural Development: We
have identified and
characterized many genes
responsible for axonal
outgrowth as well as for other
aspects of neuronal
Behavior: We are analyzing
both how the nervous system
controls behavior and how
genes specify the functioning
of a neuromuscular system.
We have used a laser
microbeam, pharmacology and
mutations to identify which
neurons control specific
behaviors. We have analyzed
how the environment and
experience modulate the
locomotory rate of C. elegans
and have discovered that the
animal’s serotonergic nervous
system plays a central role in
its response to its experience.
These studies have allowed us
to identify and analyze a novel
MIT Department of Biology: H. Robert Horvitz
ionotropic serotonin receptor(a serotonin-gated chloridechannel) and aserotonin-reuptake transportersimilar to the target of humanantidepressants (e.g., Prozac).
We have also identified genesthat control octopaminergicneurotransmission and genesthat control a two-porepotassium channel complexinvolved in musclecontraction. Human Neurologic Disease:
In collaboration with others,
we showed that one gene
responsible for the inherited
form of amyotrophic lateral
sclerosis (ALS or Lou Gehrig’s
disease) encodes the enzyme
Cu/Zn superoxide dismutase
(SOD), which catalyzes the
conversion of the free radical
superoxide to hydrogen
peroxide. We are now seeking
other genes responsible for
ALS and studying C. elegans
models of ALS and of other
human genetic neurologic
and/or aging disorders,
including mucolipidosis type
IV and a progeroid variant of
Ehlers-Danlos syndrome.

Lundquist, E., Reddien, P.,
Hartwieg, E., Horvitz, H.R. and
Bargmann, C. Three C.
Rac proteins and
several alternative Rac
regulators control axon
guidance, cell migration and
apoptotic cell phagocytosis.
Development 128, 4475-4488


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