-
Regulation
of Stem Cell Behavior
-
Cell
Type Specific Transcription Machinery and Tissue Specific Gene
Expression
-
Cell
Cycle and Cell Morphogenesis During Male Gametogenesis
-
Mechanism
of Cytokinesis
A
major focus of our work concerns the mechanisms that regulate stem cell
behavior. Many highly
differentiated but short-lived cell-types, including blood, skin, and sperm,
are produced throughout adult life from stem cells.
The central characteristic of stem cells is their remarkable,
long-term capacity to divide as relatively undifferentiated precursors while
also producing daughter cells that initiate differentiation. Understanding
the mechanisms that regulate stem cell specification and the choice between
stem cell self-renewal and differentiation is crucial for realizing the
potential of stem cells for regenerative medicine. We are using the Drosophila
male germ line as a powerful genetic system to identify both the cell
autonomous determinants and the extrinsic cell-cell interactions that govern
stem cell behavior. Our results
indicate that signals from surrounding somatic support cells specify
asymmetric division of male germ line stem cells by inducing one daughter
cell to self-renew stem cell identity while directing the other daughter
cell to differentiate.
A
second focus of our work concerns a central question in both developmental
and cell biology: How does the developmental program remodel fundamental
cellular functions like the cell cycle, the cytoskeleton, and the general
transcription machinery to give rise to specialized cell types during
cellular differentiation? We investigate the mechanisms that regulate and
mediate cellular differentiation during male gametogenesis, using
spermatogenesis in Drosophila a
powerful genetic model system. Our
current work focuses on three areas. 1) We are investigating the mechanisms
that regulate the unique program of gene expression that takes place in
primary spermatocytes in preparation for the dramatic morphogenetic events
of spermatid differentiation. We
have discovered that both progression of the meiotic cell cycle and
expression of spermatid differentiation genes are regulated by tissue
specific versions of the general PolII transcription machinery.
In addition, our work implicates components upstream of the Rb
pathway in the control of terminal differentiation.
2) We are exploring the mechanisms that regulate remodeling of
sub-cellular organelles. Our
studies revealed the first known protein mediator of mitochondrial fusion,
required for formation of specialized mitochondrial structures in spermatids.
Our current work indicates that human homologs of the Drosophila
mitofusin protein regulate mitochondrial morphology in human cells and may
play a role in apotosis as well. 3)
We are dissecting the mechanisms that remodel the actin cytoskeleton and
lead to localized assembly and constriction of the acto-myosin contractile
machinery during cytokinesis. We
have identified mutations in over 20 new genes that block different stages
of contractile ring assembly and function during male meiosis.
To investigate the underlying molecular mechanisms that regulate and
mediate cytokinesis, we are cloning selected of these genes.
Our initial results indicate that shared mechanisms involving
addition of new membrane are required for both cleavage furrow constriction
during cytokinesis and polarized cell elongation during later terminal
differentiation. |
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