Role of the FoxN1 gene as a central regulator of epidermal planar cell polarity signaling expression and function

Summary:

1. Context of the research

During development, planar cell polarity (PCP) is an important mechanism to align cells and tissues along the main axis of the body. Currently we have a known group of molecules called "PCP components" that are important for PCP establishment. Disturbing one or several of these molecules can result in PCP changes that have been proved to be linked with human diseases such as spina bifida (neural tube closure disorders), polycystic kidneys, conotruncal heart anomalies, deafness and more recently cancer. So far little is known about the molecular controlling of the expression of the PCP molecules. Furthermore, reports showed that PCP gene expression was altered in different kinds of cancers. Cancer cells are immature cells and fail to differentiate hence differentiation therapy is the major tool we are using to treat cancer. Till now if PCP can also participate cell differentiation is still not known.
Previously I have published papers documenting different mouse models that have altered skin epithelial cell differentiation that eventually contributed to skin cancer formation. Through a detail analysis of the same models I have found that the skin epidermis PCP in these mice had been altered at early embryonic stages. My results also pointed out that FoxN1, a molecule that had been reported formerly to be important for hair cell differentiation is highly expressed in differentiated cells, this might be an essential factor in controlling PCP, at least in the epidermis.

2. Aims and objectives

The aim of this study are (1) to validate which PCP component genes are under the direct control of FoxN1 and (2) to identify what is the role of the PCP gene(s) in FoxN1 mediated cell differentiation. Specific objectives will be achieved in 3 years' continuous laboratory work and close collaboration with clinicians and international institutes.

By the end of year 1, I expect to be able to achieve solid evidence for which exact PCP gene(s) is the direct target of FoxN1 and how FoxN1 regulates the expression of these molecules in the human skin epidermis.

By the end of year 2, I will try to identify if PCP genes are the key mediator of FoxN1 governed epithelial cell differentiation. In parallel I will study Cilia (one important organelle in eukaryotic cells that has been linked with PCP) formation in the skin epidermis, to understand if it can also be controlled by FoxN1.

By the end of the project (year 3), I plan to understand what is the effect of the extrinsic factor UVB on epithelial cell differentiation and its capacity for causing diseases. By focusing on the role of UVB, I will study if FoxN1 mediated PCP signaling is important for protecting the cells from UVB exposure. Finally an effort will be made to discover which chemical compounds can be used to regulate FoxN1 signaling therefore which are able to enhance cell differentiation.

3. Potential applications and benefits

Throughout this study, I expect we will gain a deeper insight of how different molecules work together to regulate cell PCP and differentiation. Not only will our knowledge in this area be enhanced but we are also likely to uncover targets for potential new therapies for PCP and cell differentiation related diseases.

Planar cell polarity (PCP) is a common mechanism in development. Currently the PCP-related diseases include neural tube closure disorders, polycystic kidneys, conotruncal heart anomalies and deafness (sensory hair cell polarity disruption-related). The vertebrate skin also provides an excellent example of PCP. Skin epidermal PCP and differentiation have been considered to be controlled by distinct mechanisms. Importantly, growing evidence suggests that PCP gene expression is disturbed in cancer epithelial cells. However the molecular and cellular mechanism of PCP gene engaging in epithelial cell differentiation has not previously been studied. Recently I have reported that suppression of mesenchymal RBPJk signaling (the key effector of the Notch pathway) resulted in hair follicle keratinocyte differentiation defects and epithelial tumors that were due to altered FoxN1 signaling in the epithelial cells, mediated by Wnt5a that is under the control of Notch/RBP-J in dermal papilla cells. Using the same models, my preliminary results show mutant mice all developed skin planar cell polarity defects. Furthermore, PCP core components have altered expression levels during epithelial cell differentiation. Finally, modulating FoxN1 signaling regulates the expression of several key PCP genes. I plan to further explore: (1) If FoxN1 plays a key role in governing the transcription of core PCP gene expression and function, and (2) Whether any PCP core components work as downstream effectors of FoxN1 to mediate epithelial cell differentiation. Different in vitro and in vivo approaches will be applied and the function of an extrinsic factor, UVB on FoxN1 mediated cell differentiation, will be examined as well. Finally a chemical compound screening will be performed to identify potent drugs that can be applied to modulate FoxN1 signaling. This work will further our knowledge of the controlling mechanism of PCP signaling and will provide competent therapeutic t

The proposed project will have significant impact on our current knowledge for the molecular controlling mechanisms of Planar Cell Polarity (PCP) and the functions of PCP genes.

Academia

Currently the controlling mechanism of PCP is a key question that remains unclear in developmental biology. Also the additional function of PCP genes in other cellular processes has not been studied so far. e.g. in the epithelial tissues, as formerly PCP and cell differentiation were considered to be two separate processes regulated by distinctive mechanisms. This research will advance our knowledge of how different cellular events are controlled by identical molecular signaling regulation axis. The same mechanism will be able to be adapted easily to the other systems. In addition, the application of findings in developmental biology to pathological situations such as cancer also provides excellent opportunities for translational research that has significant impacts on the general public and government (please see below).

General Public

PCP is a fundamental mechanism of development and when it is defective it contributes to many human diseases such as spina bifida (neural tube closure disorders), polycystic kidneys, conotruncal heart anomalies, deafness and more recently cancer. PCP changes can be the earliest cellular events leading to these diseases. The identification of new functions of PCP genes and their key controlling factors can also contribute to public health by providing potential early diagnosis and therapeutic targets for PCP related disorders.

Government

Identifying how PCP can participate in normal human development and disease initiation by interfering with cell differentiation can help to identify targets for intervention during early disease initiation. This knowledge could significantly reduce clinical costs and also improve patients' quality of life. For example, currently in the UK, total annual costs for cancer patients are over £15 billion. Differentiation therapy is one of the most desirable solutions for cancer treatment. Most of the current therapies are based on established tumors. Through screening small molecules (compounds) that can regulate FoxN1 and PCP we may identify potential future drugs that will be applied for PCP related diseases, especially cancer.

Clinician

Clinically, how to predict the outcomes and future potential accompanying diseases of patients with developmental defects is always a challenge. This is largely due to our lack of knowledge of the molecular significance of the genes involved in the specific disease. Hence the current study will be able to advance our understanding of the how potentially people with one kind of PCP disease can have more susceptibility to other kinds of disease such as cancer.

Industry

The study will involve a screen of chemical compounds that can be used to regulate FoxN1 gene mediated PCP and cell differentiation. This knowledge could be used in the future to treat PCP related diseases.