Naohiro Terada, MD, PhD
Associate Professor
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Dept. of Pathology, Immunology and Laboratory Medicine |
Currently Involved In:
Stem Cell Biology & Regenerative Medicine
Basic ES Cell Biology
The primary project in the
laboratory focuses on basic biology of embryonic stem (ES) cells. Mouse ES
cells were first isolated in 1981, and found to be pluripotent in
differentiation while maintaining the capacity for indefinite self-renewal.
Although expectation is very high for the use of ES cells or a similar
pluripotent cell population as a source of cell-based transplantation therapy
in the clinical setting, the use of ES cells as a tool for basic science
should also not be overlooked. ES cells differentiate on culture dishes, at
least in part, by recapitulating the processes seen in embryonic development.
Using this in vitro differentiation of ES cells, we have been studying
molecular mechanisms underlying early embryonic cell fate specification. In
particular, we focus on the differentiation process of ES cells into
extraembryonic primitive endoderm (see the Figure below), which represents
the event occurring within the inner cell mass of E3.5 blastocysts. By
revealing the mechanisms as to how ES cells retain or lose pluripotency, the
study will provide us with critical insight regarding how stem cells self-renew or differentiate in
general. Of interest, we and others recently demonstrated that both mouse and
human ES cells are not homogeneous in cell culture but have multiple and
overlapping heterogeneity. Moreover, these heterogeneities appear to be
essential and play a critical role for ES cell maintenance. Currently, we are
elucidating a biphasic role of the FGFR signaling in ES cell differentiation
and self-renewal.
Germ Cells, Cancer, Epigenetics
Another major focus of the lab is
on mitochondrial adenine nucleotide translocases (ANTs), which mediate the exchange
of ADP and ATP on the inner mitochondrial membrane, thus essential for energy
metabolism in eukaryotic cells. Until recently, it has been believed that
humans posses three members of the ANT family of genes, whose transcription
depends on tissue type, developmental stage, cell proliferation, and hormone
status etc. We have recently identified the fourth member of ANT,
ANT4, through ES cell research, and determined that it is expressed
exclusively in male germ cells and is particularly high during meiosis. ANT4
is conserved only in mammals, suggesting a unique and indispensable role for
this ADP/ATP carrier in mammalian germ cell development. By generating Ant4
deficient mice, we recently determined that Ant4 is essential for male germ
cell meiosis and subsequent male fertility. Although chromosomal localization
of ANT family genes indicates that ANT4 may be compensating the inactivation
of the X chromosome-linked ANT2 gene during male meiosis, ANT4 has a distinct
protein structure compared to other somatic ANTs. To this end, we are
currently working under the hypothesis that ANT4 has been uniquely adapted to
mammalian spermatogenesis and sperm function. A distinct structure of ANT4
peptide has also enabled us to predict small compounds to specifically ANT4 using a molecular docking
approach. We may be able to prove these lead compounds useful for developing
male contraceptives. Further, our recent study on transcriptional regulation
of the Ant4 gene is revealing a common molecular mechanism as to how
meiosis-specific genes are repressed in somatic tissues. Since the aberrant
expression of meiosis specific genes may lead to mitotic catastrophe and
predispose cells to oncogenic transformation, the study would become
significant in cancer biology as well.