CLEFT PALATE

Cleft lip and palate are the most common birth defect in humans

As a developmental biologist, I am intrigued by the complex morphogenetic processes that must be precisely executed to ensure that the bilateral palatal shelves grow, elevate, and fuse at the midline to ensure palate closure. When this process fails at any one of these steps, palate closure is incomplete, leading to the formation of a cleft. As a testament to how frequently this occurs, hundreds to thousands of genes (most shared between humans and mice) cause cleft palate when disrupted, and ~1/700 babies are born with cleft lip or palate, making it the most common of all birth defects.

Cell-cell adhesion molecules are a mutated in cleft palate in humans

Our existing interest in epidermal cell-cell adhesion molecules and how they influence spindle orientation motivated us to investigate the role that these adherens junction proteins play in oral development. Moreover, alterations in cell-cell adhesion are common causes of cleft lip and palate (Lough et al, JDR 2017). Specifically, in humans, alterations in the cell-cell adhesion molecule NECTIN1 causes Cleft Lip/Palate Ectodermal Dysplasia Syndrome (OMIM: CLPED1), also known as Zlotogora-Ogur Syndrome or Margarita Island Type Ectodermal Dysplasia). The nectins are a family of four transmembrane receptors that signal obligately through the adherens junction protein afadin to interact with the actin cytoskeleton. Perhaps likely due to redundancy, no single nectin mouse mutant has displayed cleft palate, thus making it difficult to model human disease. However, we have confirmed a critical role for this family of adhesion proteins in palate closure by showing that Afadin mutants display highly-penetrant cleft palate. Importantly, this requires early deletion of Afadin prior to palatogenesis, which we can uniquely accomplish using LUGGIGE.

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Ongoing questions being addressed in current studies include:

How does loss of specific nectins and afadin affect cell-cell adhesion? (collaboration with Hoffman lab @ Duke)

Which nectins are expressed in palatal epithelium and do they function redundantly?

Can expressing human disease variants of NECTIN1 using LUGGIGE induce cleft palate?