Date of Completion

5-3-2018

Embargo Period

5-2-2018

Advisors

Dr. Craig Nelson , Dr. Joseph Loturco, Dr. David Goldhamer, Dr. Joseph Crivello , Dr. Jason Gibson

Field of Study

Physiology and Neurobiology

Degree

Master of Science

Open Access

Open Access

Abstract

The world health organization estimates that craniofacial defects affect between 2-3% of all live births, with complications ranging from aesthetic issues to severe mental retardation (Marcucio 2015). It is estimated that for a pathology resulting in craniofacial aberrations, each affected individual costs society ~1 million dollars in corrective and palliative care (Singh 2014). Current investigations into genetics underlying these defects have revealed 564 human (HPO 2017) and 3297 murine (MGI 2017) genes thought to be involved in craniofacial pathologies. Facial development requires a population of cells known as Cranial Neural Crest Cells (CNCCs) to properly migrate from the neural plate border and to populate the tissue of the future face (Douarin 2007). CNCCs are multipotent progenitors that respond to extrinsic signaling to make fate choices. Dysregulation of this process can result in craniofacial pathologies, such as clefting. Not only will understanding the genetic factors behind craniofacial development allow for better treatment of craniofacial disease, but can aid in genetic counseling to ultimately save millions of dollars in healthcare costs.

Currently, discovery of genes involved with craniofacial development rely on high throughput genetic manipulations in animal models and/or epidemiological information obtained from human populations. These discoveries mainly employ top-down approaches to understand the genetics involved in craniofacial disorders. We propose that we can employ a bottom-upapproach to elucidate novel genetic components involved in normal craniofacial development to interrogate craniofacial diseases, chiefly, ones affecting craniofacial skeletal development.

Our lab’s focus is to resolve the transcriptic profile of populations of cells, using single-cell RNA sequencing during murine development. Of note is the ability of our lab to identify genes that co-vary with one another in populations of cells and are thought to coordinate genetic programs, a concept known as a metagene (Wilson 2012). Recently, our efforts have been to characterize populations of cells from theiler stage 19 (TS19) murine embryos, a developmental stage critical in craniofacial development (Kawauchi 2005). We propose three specific aims in order to evaluate craniofacial development in a bottom-up manner; (1) identify metagenes in putative CNCCs and osteoblastic progeny in our TS19 data set, (2) create a model system to interrogate CNCC metagene expression patterns and (3) perturb metagenes to broaden our understanding of CNCC fate decisions, particularly towards an osteoblastic fate.

Our proposed research will broadly impact the field by expanding methods to evaluate genetic programs guiding fate decisions. These findings will help to identify novel genes participating in craniofacial development and can be used to understand genetic dysregulation occurring in craniofacial pathologies.

Major Advisor

Dr. Craig Nelson

Download

Share

COinS