The cranial sensory placodes are important embryonic precursors that give rise to critical structures in the vertebrate head, including olfactory epithelium, lens, acoustic and vestibular organs and the cranial sensory ganglia. In addition, migrating cranial neural crest require an interaction with placodes in order to form craniofacial cartilages properly. Despite the fact that the cranial placodes have been histologically recognized for over a century and the vital contributions to cranial sensory organs have been recognized for nearly as long, very little is known about the molecular mechanisms that specify the cranial sensory progenitor cells (SPCs) or lead to individual placode identity and differentiation. One goal of this proposal is to identify the gene regulatory network that regulates the specification of multipotent placode-derived SPCs to understand the genetic hierarchy underlying cranial sensory organ formation. Damage to placode-derived structures or congenital defects of the placodes or their common precursor tissue can have a devastating effect on an individual, profoundly impairing the sense of smell, sight, hearing, balance, taste and somatothesis of the face. Recent studies have connected mutations in genes that play a central role in placode development to several craniofacial disorders. A second goal of this proposal is to identify new candidate genes that underlie craniofacial birth defects that involve placode-derived sensory structures. To accomplish these goals, we shall focus our studies on the regulation of the transcription factor Six1 for two reasons. First, mutations of Six1 result in the branchio-otic syndrome 3 (BOS3, OMIM 608389), which is characterized by craniofacial defects and hearing loss. Second, Six1 knock-out in mouse and Six1 knock-down in Xenopus and chick result in severe defects in several placode-derived structures. To accomplish our two main goals, we shall determine: 1) what genes directly regulate Six1 expression using bioinformatics, in vivo and biochemical assays;2) the epistatic relationships between Six1 and its downstream targets, relying on microarray data obtained from two different animal models;and 3) which of the genes that act down-stream of Six1 are direct targets. The proposed experiments represent a close collaboration between the Moody and Streit labs;our labs have worked in parallel on similar topics in placode development using two different animal models (Xenopus and chick, respectively). We now propose to combine our expertise to create a gene regulatory network that regulates cranial sensory precursor specification and placode development. Using two different, powerful animal models will provide the strongest information for conserved gene regulation across vertebrates that will have the most relevance to human craniofacial syndromes. This research project utilizes classical embryological approaches in the hands of two experts renowned for their studies of placode development and combines them with cutting edge technological advances. This combination of experimental strengths predict that important information regarding normal development as well as discovery of novel genetic causes of craniofacial birth defects will be forth coming from this project.

Public Health Relevance

The goal of this proposal is to utilize two vertebrate model organisms to elucidate the interactions between transcription factors that specify cranial sensory precursor cells that are required for the proper development of specialized sensory organs in the head, such as olfactory epithelium (sense of smell), lens (vision), inner ear (hearing and balance) and cranial ganglia (sense of touch on the face and oral cavity). This information is important for: 1) understanding how these important organs form;and 2) interpreting genetic mutations and human congenital syndromes. The proposed experiments will provide fundamental knowledge about the molecular regulation of an understudied aspect of embryonic development and will lead to the discovery of genes that contribute to human birth defects.

National Institute of Health (NIH)
National Institute of Dental & Craniofacial Research (NIDCR)
Research Project (R01)
Project #
Application #
Study Section
Skeletal Biology Development and Disease Study Section (SBDD)
Program Officer
Scholnick, Steven
Project Start
Project End
Budget Start
Budget End
Support Year
Fiscal Year
Total Cost
Indirect Cost
George Washington University
Anatomy/Cell Biology
Schools of Medicine
United States
Zip Code
Trevers, Katherine E; Prajapati, Ravindra S; Hintze, Mark et al. (2018) Neural induction by the node and placode induction by head mesoderm share an initial state resembling neural plate border and ES cells. Proc Natl Acad Sci U S A 115:355-360
Sullivan, Charles H; Majumdar, Himani D; Neilson, Karen M et al. (2018) Six1 and Irx1 have reciprocal interactions during cranial placode and otic vesicle formation. Dev Biol :
Hintze, Mark; Prajapati, Ravindra Singh; Tambalo, Monica et al. (2017) Cell interactions, signals and transcriptional hierarchy governing placode progenitor induction. Development 144:2810-2823
Marchak, Alexander; Grant, Paaqua A; Neilson, Karen M et al. (2017) Wbp2nl has a developmental role in establishing neural and non-neural ectodermal fates. Dev Biol 429:213-224
Neilson, Karen M; Abbruzzesse, Genevieve; Kenyon, Kristy et al. (2017) Pa2G4 is a novel Six1 co-factor that is required for neural crest and otic development. Dev Biol 421:171-182
Karpinski, Beverly A; Bryan, Corey A; Paronett, Elizabeth M et al. (2016) A cellular and molecular mosaic establishes growth and differentiation states for cranial sensory neurons. Dev Biol 415:228-241
Gaur, Shailly; Mandelbaum, Max; Herold, Mona et al. (2016) Neural transcription factors bias cleavage stage blastomeres to give rise to neural ectoderm. Genesis 54:334-49
LaMantia, Anthony-Samuel; Moody, Sally A; Maynard, Thomas M et al. (2016) Hard to swallow: Developmental biological insights into pediatric dysphagia. Dev Biol 409:329-42
Yan, Bo; Neilson, Karen M; Ranganathan, Ramya et al. (2015) Microarray identification of novel genes downstream of Six1, a critical factor in cranial placode, somite, and kidney development. Dev Dyn 244:181-210
Moody, Sally A; LaMantia, Anthony-Samuel (2015) Transcriptional regulation of cranial sensory placode development. Curr Top Dev Biol 111:301-50

Showing the most recent 10 out of 18 publications