Elucidating the developmental events that lead to the differentiation of a variety of specialized neurons is an important goal for understanding normal nervous system development, for explaining and intervening in congenital birth defects, and for designing neuronal replacement therapies for degenerative CNS diseases. The goals of this research program are to determine the molecules and cellular interactions that regulate the fate choices of embryonic progenitors to contribute to the nervous system. Using an experimental system that allows investigation of maternal molecules and cell-to-cell interactions we will test the function of localized and locally activated molecules that influence the very beginning of an embryonic cell's developmental pathway to becoming neural. To identify the maternal gene products contained in blastomere D1.1 that function in axis specification, including formation of the CNS, cDNA libraries were constructed from translatable RNAs isolated from that blastomere, and screened for pools of mRNAs that induce secondary axial structures. We identified a novel fork head (winged helix) transcription factor and several pools of dorsal axis-inducing cDNAs with this activity.
The specific aims of this proposal are to define both the maternal and zygotic functions of these new genes. The first goal will be accomplished by: a) using animal cap assays to establish where these genes lay in a signaling hierarchy, b) mis-expression and lineage analyses to determine ectopic function, c) polyadenylation assays to establish protein expression regulation and d) maternal gene knock out techniques. The second goal will be accomplish by: a) using animal cap assays to establish which known candidates upregulate or repress the zygotic expression of these new genes, and b) transgenic mis-expression studies. In addition, we identified an interaction between B-tier and C-tier blastomeres, during cleavage stages but prior to the onset of zygotic transcription, that influences whether these cell contribute to the CNS. The signaling system underlying this fate decision will be determined by targeted over-expression of signaling molecules and unique recombinations of signaling blastomeres. These studies will provide fundamental data regarding the earliest maternal regulation and cell-cell interactions that bias embryonic progenitors to give rise to neural tissues. Furthermore they will elucidate the zygotic function of several new genes that are expressed in the neural plat and establish whether these molecules are involved in establishing neuronal identity during early embryogenesis.

Agency
National Institute of Health (NIH)
Institute
National Institute of Neurological Disorders and Stroke (NINDS)
Type
Research Project (R01)
Project #
3R01NS023158-15S1
Application #
6152322
Study Section
Special Emphasis Panel (ZRG1 (01))
Program Officer
Spinella, Giovanna M
Project Start
1986-01-15
Project End
2002-12-31
Budget Start
1999-01-01
Budget End
1999-12-31
Support Year
15
Fiscal Year
1999
Total Cost
Indirect Cost
Name
George Washington University
Department
Anatomy/Cell Biology
Type
Schools of Medicine
DUNS #
City
Washington
State
DC
Country
United States
Zip Code
20052
Yan, Bo; Neilson, Karen M; Ranganathan, Ramya et al. (2015) Microarray identification of novel genes downstream of Six1, a critical factor in cranial placode, somite, and kidney development. Dev Dyn 244:181-210
Lee, Hyun-Kyung; Lee, Hyun-Shik; Moody, Sally A (2014) Neural transcription factors: from embryos to neural stem cells. Mol Cells 37:705-12
Karpinski, Beverly A; Maynard, Thomas M; Fralish, Matthew S et al. (2014) Dysphagia and disrupted cranial nerve development in a mouse model of DiGeorge (22q11) deletion syndrome. Dis Model Mech 7:245-57
Grant, Paaqua A; Yan, Bo; Johnson, Michael A et al. (2014) Novel animal pole-enriched maternal mRNAs are preferentially expressed in neural ectoderm. Dev Dyn 243:478-96
Moody, Sally A; Klein, Steven L; Karpinski, Beverley A et al. (2013) On becoming neural: what the embryo can tell us about differentiating neural stem cells. Am J Stem Cells 2:74-94
Yan, Bo; Neilson, Karen M; Moody, Sally A (2010) Microarray identification of novel downstream targets of FoxD4L1/D5, a critical component of the neural ectodermal transcriptional network. Dev Dyn 239:3467-80
Rogers, Crystal D; Moody, Sally A; Casey, Elena S (2009) Neural induction and factors that stabilize a neural fate. Birth Defects Res C Embryo Today 87:249-62
Yan, Bo; Neilson, Karen M; Moody, Sally A (2009) foxD5 plays a critical upstream role in regulating neural ectodermal fate and the onset of neural differentiation. Dev Biol 329:80-95
Yan, Bo; Neilson, Karen M; Moody, Sally A (2009) Notch signaling downstream of foxD5 promotes neural ectodermal transcription factors that inhibit neural differentiation. Dev Dyn 238:1358-65
Schlosser, Gerhard; Awtry, Tammy; Brugmann, Samantha A et al. (2008) Eya1 and Six1 promote neurogenesis in the cranial placodes in a SoxB1-dependent fashion. Dev Biol 320:199-214

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