The major area of study in the laboratory concerns
a novel class of CCCH tandem zinc finger proteins.
This protein family consists of three orthologous
proteins in mice and man. All three family members
can bind to AU-rich elements in certain mRNA species,
causing the removal of their poly(A) tails and speeding
up their breakdown. The mechanism of this effect on
mRNA stability is unknown, and is an active area of
study. The prototype protein of this family, TTP,
is involved in the physiological regulation of medically
important cytokines, such as tumor necrosis factor
alpha (TNF), and clinical studies have been initiated
to study possible TTP defects in TNF excess diseases
such as rheumatoid arthritis. As determined from gene
knockout studies, the other family members are involved
in early embryonic development; identification of
their target mRNAs is an active priority. Finally,
the molecular activities of this protein family are
being studied in model organisms expressing only a
single family member, such as Drosophila (and other
insects) and fission yeast.
A second major topic under study involves a small
family of direct substrates for protein kinase C (PKC),
consisting of MARCKS and its smaller relative, MLP.
Current projects include structure function studies
of the protein in two major systems, development of
the mouse central nervous system, and early embryogenesis
in Xenopus laevis. Approaches used include knockout
mice, and embryonic stem cells derived from them,
to study the roles of these proteins in cell migration
during brain development; other cell behaviors are
being studied in cultured neurons derived from the
stem cells. Finally, we are investigating the possibility
that mutations in the MARCKS and MLP genes are involved
in human neural tube defects, particularly at the
level of increasing a genetic predisposition to environmental
causes of these defects.
