| dc.description.abstract | Melanocytes are pigment-producing cells that colour our hair, skin and eyes.
Melanocytes are evolutionary conserved in vertebrates, and in addition to
contributing to pigmentation and pattern formation, can contribute to background
adaptation (zebrafish) and protection against harmful UV irradiation (humans). Many
of the processes involved in melanocyte development – such as migration,
proliferation and differentiation - are misregulated in melanoma. Here, I use
chemical biology in zebrafish to identify targetable pathways in melanocyte
development and regeneration, with a view to how these processes may be
misregulated in melanoma and other pigmentation syndromes.
We first wanted to address the potential for small molecules to regulate multiple
stages of melanocyte development and differentiation. In Chapter 3, I describe my
work involved in a small molecule screen for clinically active compounds that alter
melanocyte biology (Colanesi et al., 2012). In this work we have identified small-molecules
that affect melanocyte migration, differentiation, survival, morphology
and number. This is important as it highlights new pathways essential for normal
melanocyte development and consequently provides further tools in which to study
melanocytes.
Identifying the target of small molecules in vivo is a challenge in chemical biology.
In Chapter 4, I describe my contributions to understanding how 5-nitrofuran
compounds act in zebrafish (Zhou et al., 2012). My work has contributed to
understanding the activity of 5-nitrofurans is dependent upon its nitrofuran ring
structure. I have also helped confirm a conserved interaction between 5-nitrofurans
and ALDH2, which may contribute to the off-target effects observed in the clinic.
These results are important as they aid further understand of the 5-nitrofuran class of
drugs and give evidence to support combination therapy of 5-nitrofurans with
ALDH2 inhibitors as a way to overcome clinical side effects. Additionally I show
that NFN1 treatment limits ensuing melanocyte regeneration thereby suggesting a
role at the Melanocyte Stem Cell (MSC), which provides me with a key tool to study
melanocyte regeneration in zebrafish.
How tissue specific cell numbers are specified and maintained is a key question in
developmental biology. In Chapter 5, I describe the identification of the MITF gene
in the maintenance of cell cycle arrest in differentiated melanocytes (Taylor et al.,
2011). We show that the human melanoma mutation MITF4TΔ2B promotes melanocyte
division, thereby suggesting a role for melanocyte division in the pathogenesis of
melanoma. This work is valuable because it highlights Mitf as a molecular rheostat
that controls melanocyte proliferation and differentiation in living vertebrates, and
helps us to understand the role of MITF in melanoma progression.
Little is known about the pathways that control melanocyte stem cells in animals. To
identify new melanocyte stem cell pathways, I used NFN1 as the basis for a small
molecule screen for enhancers of melanocyte regeneration (Chapter 6). I find that
chemical inhibition of Phosphatase of Regenerating Liver-3 (Prl-3) in zebrafish can
enhance melanocyte regeneration. Importantly, I have found that there are an
increased number of melanocyte progenitor cells in PRL3-inhibitor treated zebrafish.
I propose that PRL-3 may control progenitor cell number in melanocyte
regeneration. This is significant because it identifies PRL-3 as a novel molecular
target controlling melanocyte progenitor cells, and identifies a new chemical tool
with which to study melanocyte differentiation from a progenitor population.
In the final chapter, I discuss how this work relates to the larger field of melanocyte
developmental biology, and the new insight it provides into the fundamental
processes of how organisms control cell number and pattern formation. In addition, I
discuss how this work may have implications for understanding and treating
melanocyte diseases, such as vitiligo (loss of melanocytes) and melanoma (cancer of
the melanocyte). | en |
