Alan P. Kenny, MD, PhD, focuses his research on elucidating the molecular mechanisms controlling the earliest stages of respiratory and digestive organ development. Available evidence suggests that early lung, liver, and pancreas lineages develop from a pool of foregut progenitor cells in the ventral endoderm. They are induced by FGF and BMP signals emanating from the cardiogenic mesenchyme during early somite stages of development through a mechanism that is highly conserved among vertebrates. Despite significant gains in our understanding of this process, fundamentally important questions remain unanswered. First, how are the common foregut organ progenitors specified? Second, how are FGF and BMP pathways spatiotemporally coordinated such that different organs are induced from the common foregut progenitor? A third and most intriguing question is - what are the endoderm genetic programs activated in response to induction from mesoderm that ultimately direct specific foregut organ development?
These questions remain unanswered mostly due to experimental limitations inherent in mouse embryos, which are small and difficult to dissect at such an early stage. Dr. Kenny uses the experimental advantages of the large, externally developing, abundant Xenopus embryos to address these critical, unresolved issues. Specifically, Dr. Kenny is testing his hypothesis that cardiogenic FGF and BMP signaling of different durations induce different organs. Dr. Kenny’s microarray experiment to identify the endodermal genes induced very early in response to mesodermal signaling. Surprisingly, several negative regulators of BMP signaling were induced early by mesoderm signaling. My preliminary work suggests the hypothesis that BMP inhibitory feedback is a critical component induced during early foregut organ progenitor development. This work should ultimately increase our understanding of normal and abnormal early fetal organ development, lending further insight into foregut malformations such as tracheoesophageal fistula and congenital diaphragmatic hernia. Additionally, this work aims to offer better means to direct human embryonic stem cells toward more foregut organ-specific cell fates for therapeutic purposes.