The endoderm germ layer gives rise to the digestive and respiratory tracts and their associated organs such as liver, pancreas, and lungs. Thanks to previous studies on different vertebrate model organisms, including frog, fish, chick, and mouse, we now have a general idea on how endoderm is formed during gastrulation, patterned along anterior/posterior (A/P) axis, induced by multiple signaling pathways and finally gives rise to the endodermal organ buds that will eventually serve critical functions in the digestive, respiratory and endocrine systems. What is more, utilizing the knowledge that was gathered from studying endodermal development in multiple model organisms, huge
and rapid advancement has been made in the area of human embryonic stem cells and induced pluripotent stem cells to direct the differentiation of these pluripotent cell types to form multiple endoderm cell types and even endodermal organs with biological functions (Cai et al., 2007; Kroon et al., 2008; Basma et al., 2009; Zhang et al., 2009; Green et al., 2011; Nostro et al., 2011).
Despite these advances, there are still many unanswered questions,
especially in the area of the molecular basis for early endoderm development,
mainly due to the fact that molecular signaling is highly dynamic and the same
factor can have a dramatically different impact on organ development with
changes of just hours in development or fractions of millimeters in the
embryonic gut tube (McLin et al., 2007; Wandzioch and Zaret, 2009; Kenny et
al., 2012). It’s critical to understand the mechanisms that regulate these
signaling dynamics, as developmental defects resulting in disrupted
endodermal organ function are the underlying cause of many congenital
diseases that affect millions of people, especially small children every year. In
addition there are still many inefficient steps in the directed differentiation of
stem cells that could benefit a lot from a better understanding of normal
organogenesis.
3
My main research interest is the development of foregut endoderm
progenitors, which gives rise to liver, pancreas, gall bladder and lung later on,
and my research goals are to understand: 1. How the level of Wnt signaling is
precisely controlled over the course of foregut patterning and organogenesis
stage; 2. How two major signaling pathways, Wnt and BMP pathway are
coordinated during foregut development; 3. How extracellular matrix (ECM)
molecule regulates the intracellular signaling cascade of multiple pathways to
control foregut development.
In Chapter one, the general introduction, I review our current
understanding of developmental processes and signaling pathways that
govern early foregut development, including endoderm formation and
subsequent patterning along the A/P axis, the role of Wnt and BMP pathways
during foregut patterning and foregut organ formation; and the role of ECM
molecules during foregut development. In Chapter two I present our published
findings that signaling through the Wnt receptor Frizzled 7 (Fzd7) stimulates
both canonical and non-canonical pathways to regulate endoderm progenitor
cell fate, proliferation and morphogenesis. In Chapter three I present my
unpublished research, which shows that the cell-surface heparin sulfate
proteoglycan (HSPG) Syndecan 4 (Sdc4) coordinates Wnt/Fzd7 and BMP
signaling in the foregut, highlighting the previously underappreciated role of
the ECM during foregut development. Last but not least, in Chapter four, I will
discuss the conclusions from my research, highlighting unanswered questions
and potential future directions. I also discuss the broader implications of my
data for how Wnt-BMP signaling may be coordinated in the extracellular space
in other developmental and disease contexts.