Morphogenesis of the face is a complex process that is regulated by a series of cellular processes that control directional growth and fusion of the facial primordia. The facial primordia exhibited highly stereotyped patterns of directional growth that allow the primordia to grow together and fuse to form the face, but the mechanisms underlying the directional outgrowth remain largely unknown. Classic models of directional growth of the face and limb bud rely on cell and tissue displacement by regionalized areas of cell proliferation. However, regional proliferation is likely to operate in concert with other processes to regulate the pattern of growth. For example, polarized cellular behaviors may contribute to directional growth of the facial primordia, as in the limb bud. In our previous research, we observed that neural crest mesenchyme is polarized and activation of signaling by Fibroblast growth factor disrupts this polarity, which is associated with altered outgrowth of the facial primordia, and this may be due to alterations in directional cell movements within the developing facial complex. As cells move, they generate forces that are transmitted along the extracellular matrix (ECM) within the mesenchyme and the basement membrane (BM) underlying the surface epithelium. In humans, mutations in genes comprising the ECM and BM have been implicated in orofacial clefting, but the mechanism is unknown. Here, we propose that Fgf signaling produces variation in the distribution of ECM and BM molecules, which create regions of compliance and resistance that allow different regions of the face to resist deformation (nasal pit) or to allow deformation to occur (globular process). We will test this idea in two specific aims. First, we will assess the effect of Fgf on the distribution of components of the ECM and the BM, and we will assess cellular changes in the surface epithelium. Second, we will use atomic force microscopy to map the tissue material properties across regions of the developing upper jaw in order to determine the extent to which the distribution of the ECM and BM components is associated with changes in stiffness of the developing facial regions that either resist or undergo deformation. Physical forces are involved in morphogenesis and this work will be the first to directly measure and map the forces that are generated during directional outgrowth of the developing upper jaw. We chose to examine the developing upper jaw, because disruption to directional growth in this region contributes to craniofacial birth defects, such as cleft lip and palate. Hence, understanding how directional growth is controlled in this region is important for understanding the etiology of birth defects in this region of the embryo.

Public Health Relevance

Physical forces are required for directional outgrowth of the facial primordia in order for the face to form correctly. Changes that alter these forces are likely to lead to aberrant growth and facial malformations such as cleft lip and palate. These forces create physical properties in tissues that can be measured, and our goal is to create a 4- dimensional map of these tissue properties during facial development.

National Institute of Health (NIH)
National Institute of Dental & Craniofacial Research (NIDCR)
Exploratory/Developmental Grants (R21)
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Special Emphasis Panel (ZRG1)
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Stein, Kathryn K
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University of California San Francisco
Schools of Medicine
San Francisco
United States
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