Tissue morphogenesis is a highly organized and evolutionarily conserved process controlled by the temporal and tissue-specific activation of signal transduction pathways. Vertebrate eyelid morphogenesis undergoes a common process of transient eyelid closure, resulting in closed eyelids that enclose a mucin-enriched conjunctiva sac protecting corneal maturation and development. In mice, eyelid closure takes place at embryonic day 16 (E16) and its re-opening occurs at postnatal day (P)12-14;thus, embryonic eyelid closure defects always result in an eye-open at birth (EOB) phenotype that is easily traceable at birth. Genetic mutant mice displaying EOB therefore constitute unique models to study the molecular factors and complex regulatory mechanisms underlying eyelid morphogenesis. The MAP3 kinase 1 (MAP3K1, also known as MEKK1), an """"""""eyelid closure factor"""""""", is responsible for transmission morphogenetic activin B signals to Jun N-terminal kinases (JNKs). JNK in turn phosphorylates transcription factor c-Jun to regulate gene expression events involved in eyelid closure. While activation of the MAP3K1-JNK/Jun pathway by activin B leads to epithelial cell migration, blocking this pathway in the Activin ?B-/-, Map3k1-/- and skin-specific-c-Jun-/- mice, or reduction of the signal transmission efficiency by this pathway in Map3k1+/-Jnk1-/- and Map3k1+/-Jnk1+/-Jnk2+/- compound mutant mice, all result in defective epithelial cell migration and EOB phenotypes. Despite of the clear contribution of the JNK/Jun pathway, the morphogenetic effects of MAP3K1 depend largely on JNK- independent pathways and crosstalks with other """"""""eyelid closure factors"""""""". Based on the findings that MAP3K1 is specifically expressed in the developing eyelid tip epithelial cells, we hypothesize that MAP3K1 is a master gene that coordinates multiple signaling pathways for eyelid epithelial morphogenesis and closure. The proposed studies will use genetic and molecular approaches in combination with systems biology to understand how MAP3K1 orchestrates complex signaling networks in ocular surface morphogenesis. We propose 3 specific aims: (1) to elucidate transcription factor recruitment and epigenetic modifications as mechanisms for Map3k1 promoter activation thereby connecting physiological/environmental factors to eyelid closure;(2) to delineate the downstream pathways responsible for MAP3K1-mediated gene expression;and (3) to understand how MAP3K1 crosstalk with the Smad pathway in coordinating transcription programs for eyelid closure. Human eyelid undergoes strikingly similar morphogenetic processes;however, unlike in mice, eyelid closure and re-opening in humans is entirely accomplished in utero, making it impossible to clinically diagnose eyelid closure defects. Identifying genetic and epigenetic changes associated with eyelid closure defect in mice therefore will offer useful prognostic tool for related congenital ocular diseases in human. Information derived from this work will pave the way for further investigation of genetic and environmental interactions in ocular surface development and identification of the etiology of congenital corneal anomalies.

Public Health Relevance

It is a major challenge to understand the mechanism and etiology of human developmental diseases. Results from the proposed work will provide basic understanding and useful prognostic tool for identifying the genetic and epigenetic causes of congenital corneal anomalies in human. Furthermore, our work may lead to mechanistic insights into numerous physiopathological processes in which MAP3K1 participates, such as wound healing, angiogenesis and tumor metastasis.

Agency
National Institute of Health (NIH)
Institute
National Eye Institute (NEI)
Type
Research Project (R01)
Project #
5R01EY015227-09
Application #
8281578
Study Section
Anterior Eye Disease Study Section (AED)
Program Officer
Mckie, George Ann
Project Start
2004-02-01
Project End
2014-05-31
Budget Start
2012-06-01
Budget End
2014-05-31
Support Year
9
Fiscal Year
2012
Total Cost
$357,252
Indirect Cost
$119,652
Name
University of Cincinnati
Department
Public Health & Prev Medicine
Type
Schools of Medicine
DUNS #
041064767
City
Cincinnati
State
OH
Country
United States
Zip Code
45221
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