Project Summary/Abstract
In the U.S., more than 10% of infants are born with dental anomalies, including tooth agenesis, malformation,
and enamel dysplasia (ED). The study of tooth development is critical for understanding these congenital
disorders and developing novel therapies and treatments, and thus has implications for oral health. However,
the transcriptional and epigenetic mechanisms that control tooth development is not well understood. The long-
term goal is to identify and characterize the transcription factors that function as important regulators of tooth
development in health and disease. The objective of this proposal is to understand the transcriptional and
epigenetic regulatory mechanisms underlying tooth enamel development and to address why loss-of-function
mutations of the p63 gene cause tooth anomalies, including ED. p63 is a master transcription factor of ectodermal
development and homeostasis, as evidenced by ectodermal dysplasia in individuals with p63 mutations, often
involving ED and other dental anomalies. However, the role of ΔNp63, the major isoform of p63, and the
mechanisms by which ΔNp63 regulates the chromatin and transcriptional regulatory environment in tooth
development is completely unknown due to lack of targeted genetic systems. In response to this need, a well-
defined ΔNp63 knockout mouse model was generated to perform robust, inducible deletion of ΔNp63 in the
developing enamel organ. Based on preliminary data and re-analysis of published work by others, it is
hypothesized that p63 functions as a major regulator of tooth enamel development by comprehensively activating
its target genes, which are essential for driving earlier cell fate specification and later cell differentiation events
in the enamel organ cells. Using genomics and epigenomics approaches and a newly developed mouse model
of ED in ectodermal dysplasia, in which ΔNp63 knockout is induced during tooth development, three important
questions will be addressed. Aim 1 will define the developmental mechanisms that require p63 action during
tooth development. Aim 2 willdefine the molecular mechanisms by which p63 directs tooth development. Finally,
Aim 3 will identify the cell-state transition dynamics and the underlying epigenetic mechanism governed by
ΔNp63 in tooth development. Collectively, these experiments will define the fundamental mechanisms that
govern tooth enamel development on a broad and dynamic scale, which will provide foundational information
essential for developing better ways to diagnose, treat, and prevent congenital and acquired dental disorders.
