The long term goal of this proposal is to define the roles of Bone Morphogenetic Proteins (BMPs), members of the TGF- superfamily of secreted signaling molecules, during mammalian eye development. BMPs have been implicated in many aspects of embryonic inductive tissue interactions. In particular, we have recently shown that one family member, Bmp4, plays an essential role during lens induction in the mouse embryo. In recent studies, chromosomal deletions in humans at 14q22- q23, where the BMP4 gene is mapped, have been linked with dominant anopthalmia and pituitary hypoplasia. Moreover, it has been shown that another family member, Bmp7, is required for normal eye development in the mouse. However, the molecular mechanisms by which BMPs regulate specific processes in vertebrate eye development are poorly understood. Here, we propose genetic and experimental embryological approaches to address this question, focusing on the roles of Bmp4 and a type-I Bmp receptor, Alk3. We will test the following three hypotheses; (1) that Bmp4 function is required, not only during lens induction, but also during subsequent steps in eye formation, (2) that Bmp4 and another signaling factor, Fgf15, directly mediate the lens inductive signal of the optic vesicle, (3) and that Bmp signaling is required independently in both the lens ectoderm and the retinal neuroectoderm during early eye development. Our strategy utilizes an embryonic eye explant culture technique we have established. We will treat both mutant and wildtype embryonic eye tissues with exogenous Bmp4 and/or Fgf15 proteins to explore their functions in eye formation. Furthermore, we will generate mouse embryos that lack Alk3 receptor function specifically in the developing eye using the Cre-loxP system for conditional gene disruption. The original homozygous AIk3 mutation causes pre-gastrulation embryonic lethality, and therefore the eye specific gene disruption is crucial for studying function of this gene during embryonic eye development. The embryos generated by this technique will provide mutant eye tissues which will be used for recombination organ cultures to study tissue-type specific functions of BMP signaling. These studies will contribute significantly to our understanding of the fundamental roles of secreted signaling molecules in mammalian eye development. Moreover, the results will shed light on the possibility that abnormal regulation of intercellular signaling contributes to congenital eye defects and associated postnatal eye dysfunctions in humans.

Agency
National Institute of Health (NIH)
Institute
National Eye Institute (NEI)
Type
Research Project (R01)
Project #
5R01EY013128-03
Application #
6490007
Study Section
Visual Sciences A Study Section (VISA)
Program Officer
Liberman, Ellen S
Project Start
2000-01-01
Project End
2004-12-31
Budget Start
2002-01-01
Budget End
2002-12-31
Support Year
3
Fiscal Year
2002
Total Cost
$234,277
Indirect Cost
Name
University of Texas MD Anderson Cancer Center
Department
Biochemistry
Type
Other Domestic Higher Education
DUNS #
001910777
City
Houston
State
TX
Country
United States
Zip Code
77030
Murali, Deepa; Kawaguchi-Niida, Motoko; Deng, Chu-Xia et al. (2011) Smad4 is required predominantly in the developmental processes dependent on the BMP branch of the TGF-ýý signaling system in the embryonic mouse retina. Invest Ophthalmol Vis Sci 52:2930-7
Satoh, Shinya; Tang, Ke; Iida, Atsumi et al. (2009) The spatial patterning of mouse cone opsin expression is regulated by bone morphogenetic protein signaling through downstream effector COUP-TF nuclear receptors. J Neurosci 29:12401-11
Poche, Ross A; Furuta, Yasuhide; Chaboissier, Marie-Christine et al. (2008) Sox9 is expressed in mouse multipotent retinal progenitor cells and functions in Muller glial cell development. J Comp Neurol 510:237-50
Poche, Ross A; Raven, Mary A; Kwan, Kin Ming et al. (2008) Somal positioning and dendritic growth of horizontal cells are regulated by interactions with homotypic neighbors. Eur J Neurosci 27:1607-14
Mao, Chai-An; Kiyama, Takae; Pan, Ping et al. (2008) Eomesodermin, a target gene of Pou4f2, is required for retinal ganglion cell and optic nerve development in the mouse. Development 135:271-80
Poche, Ross A; Kwan, Kin Ming; Raven, Mary A et al. (2007) Lim1 is essential for the correct laminar positioning of retinal horizontal cells. J Neurosci 27:14099-107
Vincentz, Joshua W; McWhirter, John R; Murre, Cornelis et al. (2005) Fgf15 is required for proper morphogenesis of the mouse cardiac outflow tract. Genesis 41:192-201
Murali, Deepa; Yoshikawa, Shunichi; Corrigan, Rebecca R et al. (2005) Distinct developmental programs require different levels of Bmp signaling during mouse retinal development. Development 132:913-23
Furuta, Yasuhide; Behringer, Richard R (2005) Recent innovations in tissue-specific gene modifications in the mouse. Birth Defects Res C Embryo Today 75:43-57
Lagutin, O; Zhu, C C; Furuta, Y et al. (2001) Six3 promotes the formation of ectopic optic vesicle-like structures in mouse embryos. Dev Dyn 221:342-9