Research Abstract

The step by step differentiation of embryonic cells into different types of neurons lays the foundation for our sensory responses, motor commands, and cognitive behaviors. Our research explores this exquisite differentiation program in mammals using a combination of genetic and molecular biological methods. While the generation of such neural diversity is a complex process culminating in the most sophisticated of wiring circuits, one simplifying approach is to start by tracking the migration and differentiation paths taken by specific sets of cells originating from primitive neuroectoderm. Towards this goal, our lab has pioneered genetic tools to study progenitor-progeny cell relationships in the mouse. We are now applying these tools in full to study development of those brainstem neurons (nuclei) which provide the chief input to the cerebellum, and which collectively are called the precerebellar system.

In addition to studying neural development, we have initiated genetic experiments to uncover more general determinants of tissue pattern. Using insertional mutagenesis, we have created mutant mouse stocks that exhibit developmental defects ranging from skeletal abnormalities to hair and thymic defects. We are currently using large-insert DNA clones that span the transgene insertions to identify the affected genes. Through this approach, we have identified a BMP receptor that is the physiologic transducer mediating the development of digit cartilages. Transcriptional regulation of this gene has proven to be interesting and may represent a driving force in the evolution of distal limb form.

Publications

• Hunter NL, Dymecki SM.Molecularly and temporally separable lineages form the hindbrain roof plate and contribute differentially to the choroid plexus.Development 2007 Oct;134(19):3449-60.
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• Dymecki SM, Kim JC.Molecular neuroanatomy's "Three Gs": a primer.Neuron 2007 Apr 5;54(1):17-34.
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• Farago AF, Awatramani RB, Dymecki SM.Assembly of the brainstem cochlear nuclear complex is revealed by intersectional and subtractive genetic fate maps.Neuron 2006 Apr 20;50(2):205-18.
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• Landsberg RL, Awatramani RB, Hunter NL, Farago AF, DiPietrantonio HJ, Rodriguez CI, Dymecki SM.Hindbrain rhombic lip is comprised of discrete progenitor cell populations allocated by Pax6.Neuron 2005 Dec 22;48(6):933-47.
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• Hunter NL, Hikasa H, Dymecki SM, Sokol SY.Vertebrate homologues of Frodo are dynamically expressed during embryonic development in tissues undergoing extensive morphogenetic movements.Dev Dyn 2006 Jan;235(1):279-84.
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• Hunter NL, Awatramani RB, Farley FW, Dymecki SM.Ligand-activated Flpe for temporally regulated gene modifications.Genesis 2005 Mar;41(3):99-109.
  15729687
• Branda CS, Dymecki SM.Talking about a revolution: The impact of site-specific recombinases on genetic analyses in mice.Dev Cell 2004 Jan;6(1):7-28.
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• Awatramani R, Soriano P, Rodriguez C, Mai JJ, Dymecki SM.Cryptic boundaries in roof plate and choroid plexus identified by intersectional gene activation.Nat Genet 2003 Sep;35(1):70-5.
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• Dymecki SM, Rodriguez CI, Awatramani RB.Switching on lineage tracers using site-specific recombination.Methods Mol Biol 2002;185:309-34.
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• Awatramani R, Soriano P, Mai JJ, Dymecki S.An Flp indicator mouse expressing alkaline phosphatase from the ROSA26 locus.Nat Genet 2001 Nov;29(3):257-9.
  11687793
• Farley FW, Soriano P, Steffen LS, Dymecki SM.Widespread recombinase expression using FLPeR (flipper) mice.Genesis 2000 Nov-Dec;28(3-4):106-10.
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• Rodriguez CI, Dymecki SM.Origin of the precerebellar system.Neuron 2000 Sep;27(3):475-86.
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• Rodríguez CI, Buchholz F, Galloway J, Sequerra R, Kasper J, Ayala R, Stewart AF, Dymecki SM.High-efficiency deleter mice show that FLPe is an alternative to Cre-loxP.Nat Genet 2000 Jun;25(2):139-40.
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• Baur ST, Mai JJ, Dymecki SM.Combinatorial signaling through BMP receptor IB and GDF5: shaping of the distal mouse limb and the genetics of distal limb diversity.Development 2000 Feb;127(3):605-19.
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• Dymecki SM, Tomasiewicz H.Using Flp-recombinase to characterize expansion of Wnt1-expressing neural progenitors in the mouse.Dev Biol 1998 Sep 1;201(1):57-65.
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• Dymecki SM.Flp recombinase promotes site-specific DNA recombination in embryonic stem cells and transgenic mice.Proc Natl Acad Sci U S A 1996 Jun 11;93(12):6191-6.
  8650242
• Dymecki SM.A modular set of Flp, FRT and lacZ fusion vectors for manipulating genes by site-specific recombination.Gene 1996 Jun 1;171(2):197-201.
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• Dymecki SM, Zwollo P, Zeller K, Kuhajda FP, Desiderio SV.Structure and developmental regulation of the B-lymphoid tyrosine kinase gene blk.J Biol Chem 1992 Mar 5;267(7):4815-23.
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• Wilson RB, Kiledjian M, Shen CP, Benezra R, Zwollo P, Dymecki SM, Desiderio SV, Kadesch T.Repression of immunoglobulin enhancers by the helix-loop-helix protein Id: implications for B-lymphoid-cell development.Mol Cell Biol 1991 Dec;11(12):6185-91.
  1944284
• Kozak CA, Dymecki SM, Niederhuber JE, Desiderio SV.Genetic mapping of the gene for a novel tyrosine kinase, Blk, to mouse chromosome 14.Genomics 1991 Apr;9(4):762-4.
  2037301
• Dymecki SM, Niederhuber JE, Desiderio SV.Specific expression of a tyrosine kinase gene, blk, in B lymphoid cells.Science 1990 Jan 19;247(4940):332-6.
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