The proposal is concerned with studies designed to analyze both in vitro and in vivo, the function of Brn-3b, a POU-domain transcription factor, in RGC development, and to explore underlying mechanisms for RGC degeneration under pathological conditions using the brn-3b gene locus as a molecular tool. First, transcriptional properties and structure/function relationships of Brnb-3b will be analyzed using biochemical approaches including gel mobility shift, methylation interference foot printing, and co-transfection transcription assays. These in vitro studies will provide initial information on how Brn-3b may specifically control its target gene expression in RGC development. Secondly, various histochemical and immunochemical approaches will be utilized to investigated whether Brn-3b is activated in dividing retinoblasts, and to compare cell proliferation and death between Brn-3b (+/+) and (-/-) retinas. These in vivo studies are expected to gain crucial information regarding the timing and mode of Brn-3b function during RGC development. Thirdly, Brb-3b will be replaced by homologous recombination in mice with the alkaline phosphatase reporter to examine the projections of axons, or with bcl-2 gene to study rescue of apoptosis in Brn-3b-expressing RGCs. The resulting data will help in understanding the function of Brn-3b in RGCs, and may also shed light on degeneration of RGCs in pathological conditions. Together, the proposed studies on Brn-3b function will provide fundamental insights into the molecular mechanism that control mammalian retinal development. In the long term, the information should help better understand the mechanisms leading to certain blinding disorders, and also may provide new directions for treatment modalities.

Agency
National Institute of Health (NIH)
Institute
National Eye Institute (NEI)
Type
Research Project (R01)
Project #
5R01EY012020-04
Application #
6350870
Study Section
Visual Sciences C Study Section (VISC)
Program Officer
Hunter, Chyren
Project Start
1998-02-01
Project End
2002-09-29
Budget Start
2001-02-01
Budget End
2002-09-29
Support Year
4
Fiscal Year
2001
Total Cost
$244,694
Indirect Cost
Name
University of Medicine & Dentistry of NJ
Department
Pediatrics
Type
Schools of Medicine
DUNS #
622146454
City
Piscataway
State
NJ
Country
United States
Zip Code
08854
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Misra, Kamana; Luo, Huijun; Li, Shengguo et al. (2014) Asymmetric activation of Dll4-Notch signaling by Foxn4 and proneural factors activates BMP/TGF? signaling to specify V2b interneurons in the spinal cord. Development 141:187-98
Wu, Fuguo; Li, Renzhong; Umino, Yumiko et al. (2013) Onecut1 is essential for horizontal cell genesis and retinal integrity. J Neurosci 33:13053-65, 13065a
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Xiang, Mengqing; Li, Shengguo (2013) Foxn4: a multi-faceted transcriptional regulator of cell fates in vertebrate development. Sci China Life Sci 56:985-93
Jin, Kangxin; Xiang, Mengqing (2012) In vitro explant culture and related protocols for the study of mouse retinal development. Methods Mol Biol 884:155-65
Luo, Huijun; Jin, Kangxin; Xie, Zhenhui et al. (2012) Forkhead box N4 (Foxn4) activates Dll4-Notch signaling to suppress photoreceptor cell fates of early retinal progenitors. Proc Natl Acad Sci U S A 109:E553-62
Zou, Min; Li, Shengguo; Klein, William H et al. (2012) Brn3a/Pou4f1 regulates dorsal root ganglion sensory neuron specification and axonal projection into the spinal cord. Dev Biol 364:114-27
Li, Shengguo; Xiang, Mengqing (2011) Foxn4 influences alveologenesis during lung development. Dev Dyn 240:1512-7

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