The cranial placodes are transient embryonic structures that eventually develop into portions of the sense organs and the anterior pituitary, a major endocrine gland. These placodes arise from the ectoderm, one of the three germ layers, which is known to give rise to the epidermis, brain, and spinal cord. The placodes develop in a small region that is flanked by the developing brain and epidermis. Currently we understand very little of how these transient structures develop in humans. To gain better insight into this process, this project aims to determine the underlying molecular mechanisms that restrict the ectoderm to a non-neural fate and allow it to develop into the different placodes. Due to the early time points in which these tissues arise, development will be modeled using human embryonic stem cells. Stem cells will be subjected to different culture conditions to determine the optimal conditions to derive first non-neural ectoderm, followed by pre-placodal ectoderm and finally the different placodes. All of these tissues are defined by a distinct set of genes, which will be analyzed for co-expression at single cell resolution. This knowledge can be used to study how defects in genes alter placode development. As a step towards this, we will engineer an EYA1 knockout human embryonic stem cell line and assay changes in the transcriptional profile of these cells during placode development at single cell resolution. What we learn from this research has broad implications for study of human disease affecting the sensory organ systems, including the inner ear.
Hearing loss is the most common sensory deficit in the developed world, of which many cases have a genetic component. Thirty percent of these genetic forms are syndromic and occur in conjunction with anomalies in other organ systems including those derived from the different cranial placodes. The goal of this research is to understand the molecular mechanisms involved in development of the human cranial placodes, to better understand patient-specific genetic mutations that cause these syndromic forms of hearing loss.
| Ealy, Megan; Ellwanger, Daniel C; Kosaric, Nina et al. (2016) Single-cell analysis delineates a trajectory toward the human early otic lineage. Proc Natl Acad Sci U S A 113:8508-13 |
| Ronaghi, Mohammad; Nasr, Marjan; Ealy, Megan et al. (2014) Inner ear hair cell-like cells from human embryonic stem cells. Stem Cells Dev 23:1275-84 |
