PD Dr. Kerry L. Tucker

Research Summary

Our laboratory is concerned with several aspects of neurogenesis and nerve outgrowth in the developing murine nervous system. In the cortex, we are working with several mutants involved in the trafficking of developmentally relevant signalling molecules within primary cilia. We are also investigating the role that histone deacetylases play in the development of the forebrain. In the periphery, we employ an organotypic slice culture system to manipulate and image spinal nerve innervation into the forelimb.

PD Dr. Kerry Tucker

  • 1990: B.A. in Biochemistry, Harvard College, Cambridge, Mass., USA
  • 1997: Ph.D. in Biology, Massachusetts Institute of Technology, Cambridge, Mass., USA
  • 1997-2002: Postdoctoral fellow, MPI for Neurobiology, Martinsried, Germany and Friedrich Miescher Institute, Basel, Switzerland
  • since 2003: Junior Group Leader, Interdisciplinary Center for Neurosciences, University of Heidelberg, Germany
  • 2011: Habilitation in Molecular Biology, University of Heidelberg, Faculty of Biosciences

Group Members

PhD-Students:
Christian Gojak,
Evangelia Tasouri
Kathrin Weissmüller
Marc Willaredt

Scientist:
C. Lulu Bradford
Laurea Student:
Valentina Iannizzotto
Undergraduates:
Lisa Langejürgen,
Marina Nikolic
Johannes Reiner

Technician:
Inge Frommer

Current projects

Essential roles for primary cilia in the development of the central nervous system

Primary cilia have recently been implicated as crucial sites of signal transduction and protein processing that are important for a wide range of developmental functions (Fig. 1).

We have discovered an essential role of primary cilia in forebrain development. The recessive mutation cobblestone (cbs) was identified in an ENU-based mouse mutagenesis screen and is distinguished by cortical heterotopias, appearing at 10.5 d.p.c. as protrusions from the pial surface of the dorsal forebrain. Homozygous mutants showed defects in the formation of the dorsomedial telencephalon, including an evagination of the ventricular zone that leads to the formation of folds within the cortex and thereby to the formation of the heterotopias (Fig. 2). In situ hybridization analysis indicated the presence of the choroid plexus, cortical hem and hippocampal anlage, but the morphology of these structures was severely disturbed. In contrast, development of the ventral forebrain appeared largely normal. Standard genetic mapping approaches and classical complementation analysis have identified cbs as a hypomorphic mutation in the Ift88 gene. The Ift88 protein plays an important role in the construction and maintenance of both primary and motile cilia, acting in a complex that is responsible for the intraflagellar transport of protein cargos. Northern blot, real time RT-PCR, and Western blot analysis showed a 70-80% decrease in levels of the Ift88 mRNA and protein, respectively, indicating a hypomorphic allele. Altered processing of the transcription factor Gli3 and defects in Sonic hedgehog signaling have been observed in the brains of cbs mutants, while other developmental pathways causing this pleiotropic phenotype are currently under investigation.

Transgenic mouse lines expressing modulators of Rho GTPase function

We have generated a series of mouse lines in which all postmitotic neurons express modulators of Rho GTPase function. The first line we have derived expresses a dominant negative inhibitor of RhoA in which amino acid 19 has been substituted to asparagine (N19-RhoA). Through an unknown mechanism, this results in an overrepresentation of neurons in all layers of the cerebral cortex, when analyzed at maturity. As we have not found defects in layering identity so far, we believe the cause to lie in the regulation of developmentally-occurring postnatal apoptosis, and this is currently being examined.

Histone deacetylases control neurogenesis in embryonic brain

Histone-modifying enzymes are essential for a wide variety of cellular processes dependent upon gene regulation. Histone deacetylases (HDACs) lead to the compaction of chromatin and subsequent silencing of gene transcription, and they have recently been implicated in a diversity of postnatal functions and dysfunctions in the brain including ocular dominance plasticity, the consolidation of memory in the hippocampus, epileptic seizures, and depression. We have investigated their role in the development of neurons in embryonic mouse brain. As a wide variety of HDACs are expressed in differentiating neural progenitor cells, we have taken a pharmacological approach to inhibit multiple family members. Inhibition of class I and II HDACs in developing mouse embryos with trichostatin A resulted in a dramatic reduction in neurogenesis in the striatum and a modest increase in neurogenesis in the cortex. A reduction in neurogenesis in striatum-derived neural precursors was accompanied by an increase in the production of immature astrocytes. We have shown that HDACs control neurogenesis by inhibition of the bone morphogenetic protein BMP2/4 signaling pathway. HDACs function at the transcriptional level by inhibiting and promoting, respectively, the expression of Bmp2 and Smad7, an intracellular inhibitor of BMP signaling. Inhibition of the BMP2/4 signaling pathway restores normal levels of neurogenesis and astrogliogenesis to both striatal and cortical cultures in which HDACs are inhibited. Our results demonstrate a transcriptionally-based regulation of BMP2/4 signaling by HDACs both in vivo and in vitro that is critical for striatal neurogenesis and that modulates cortical neurogenesis. This suggests that HDACs may regulate the developmental switch from neurogenesis to astrogliogenesis that occurs in late gestation. We are pursuing this question through identification of the responsible HDAC genes, their interaction partners, and their molecular targets.

Publications

Original Research Articles

1) Tucker K L; Nathanson K; Kirchhausen T (1990).

Sequence of the rat alpha-c large chain of the clathrin-associated protein complex AP-2.

Nucleic Acids Res, 18(17):5306

 

2) Assaad F; Tucker K L; Signer E (1993).

Epigenetic repeat-induced gene silencing (RIGS). in Arabidopsis.

Plant Mol Biol, 22(6):1067-1085

 

3) Tucker K L; Talbot D; Lee M A; Leonhardt H;  Jaenisch R (1996).

Complementation of methylation deficiency in embryonic stem cells by a DNA methyltransferase mini-gene.

Proc Natl Acad Sci USA, 93(23):12920-12925

 

4) Tucker K L; Beard C; Dausman J; Jackson-Grusby L; Laird P; Lei H; Li E; Jaenisch R (1996).

Germ-line passage is required for establishment of methylation and expression patterns of imprinted but not of nonimprinted genes.

Genes Dev, 10(8):1008-1020

 

5) Tucker K L; Wang Y; Dausman J;  Jaenisch R (1997).

A transgenic mouse strain expressing four drug-selectable marker genes.

Nucleic Acids Res, 25(18):3745-3746

 

6) Yamashita T; Tucker K L; Barde Y-A (1999).

Neurotrophin binding to the p75 receptor modulates Rho activity and axonal outgrowth.

Neuron, 24(3):585-593

 

7) Tucker K L; Meyer M; Barde Y-A (2001).

Neurotrophins are required for nerve growth during development.

Nat Neurosci, 4(1): 29-37

 

8) Heins N; Malatesta P; Cecconi F; Nakafuku M; Tucker K L; Hack M; Chapouton P; Barde Y-A; Goetz M (2002).

Glial cells generate neurons: the role of the transcription factor Pax6.

Nat Neurosci, 5(4):308-315

 

9) Wernig M; Tucker K L; Gornik V; Schneiders A; Buschwald R; Wiestler O D; Barde Y-A; Bruestle O (2002).

Tau EGFP embryonic stem cells: An efficient tool for neuronal lineage selection and transplantation.

J Neurosci Res, 69(6):918-924

 

10) Andorfer C; Kress Y; Espinoza M; de Silva R; Tucker K L; Barde Y-A; Duff K; Davies P (2003).

Hyperphosphorylation and aggregation of tau in mice expressing normal human tau isoforms.

J Neurochem, 86(3):582-590

 

11) Benninger F.; Beck H; Wernig M; Tucker K L; Brüstle O; Scheffler B (2003).

Functional integration of embryonic stem cell-derived neurons in hippocampal slice cultures.

J Neurosci, 23(18):7075-7083

 

12) Wernig M; Benninger F; Schmandt T; Rade M; Tucker K L; Bussow H; Beck H; Brüstle O (2004).

Functional integration of embryonic stem cell-derived neurons in vivo.

J Neurosci, 24(22):5258-5268

 

13) Korets-Smith E; Lindemann L; Tucker K L; Jiang C; Kabacs N; Belteki G; Haigh J; Gertsenstein M; Nagy A (2004).

Cre recombinase specificity defined by the tau locus.

Genesis, 40(3):131-138

 

14) Bibel M; Richter J; Schrenk K; Tucker K L; Staiger V; Korte M; Götz M;  Barde Y-A (2004).

Differentiation of mouse embryonic stem cells into a defined neuronal lineage.

Nat Neurosci, 7(9):1003-1009

 

15) Plachta N; Bibel M; Tucker K L; Barde Y-A (2004).

Developmental potential of defined neuronal progenitors derived from mouse embryonic stem cells.

Development, 131(21):5449-5456

 

16) Gao L; Tucker K L; Andreadis A (2005).

Transcriptional regulation of the mouse microtubule-associated protein tau.

Biochim Biophys Acta, 1681(2-3):175-81

 

17) Brachmann I; Jakubick V C; Shaked M; Unsicker K; Tucker K L (2007).

A simple slice culture system for the imaging of nerve development in embryonic mouse.

Dev Dyn, 236(12):3514-3523

 

18) Shakèd M; Weissmüller K; Svoboda H; Hortschansky P; Nishino N; Wölfl S; Tucker K L (2008).

Histone deacetylases control neurogenesis in embryonic brain by inhibition of BMP2/4 signaling.

PLoS One, 3(7): e2668. doi:10.1371/journal.pone.0002668

 

19) Willaredt M A; Hasenpusch-Theil K; Gardner H A R; Kitanovic I; Hirschfeld-Warneken V C; Gojak C P; Gorgas K; Bradford C L; Spatz J; Wölfl S; Theil T; Tucker K L (2008).

A crucial role for primary cilia in cortical morphogenesis.

J Neurosci, 28(48):12887-12900

 

20) Sanno H; Shen X; Kuru N; Bormuth I; Bobsin K; Gardner H A R G; Komljenovic D; Tarabykin V; Erzurumlu R;  Tucker K L (2010).

Control of postnatal apoptosis in the neocortex by RhoA-subfamily GTPases determines neuronal density.

J Neurosci, 30(12):4221-4231

 

21) Brachmann I; Tucker K L (2011).

Organotypic slice culture of GFP-expressing mouse embryos for real-time imaging of peripheral nerve outgrowth.

J Vis Exp, 49: doi: 10.3791/2309 (http://www.jove.com/details.stp?id=2309).

 

Review Articles

1) Tucker K L (2001)

In vivo imaging of the mammalian nervous system using fluorescent proteins.

Histochem Cell Biol, 115(1):31-39.

 

2) Tucker K L (2001)

Methylated cytosine and the brain: A new base for neuroscience.

Neuron, 30(3):649-652.

 

3) Tucker K L (2002)

Neurotrophins and the control of axonal outgrowth.

Panminerva Med, 44(4):325-333.

 

4) Wolff S B E; Tucker K L (2008).

Die Rolle der Histon-Acetylierung für Lernen und Gedächtnis.

Neuroforum, 4/08:274-279.

 

5) Tasouri E; Tucker K L (2011)

Primary cilia and organogenesis: Is Sonic hedgehog the only sculptor?

Cell Tissue Res, 345(1):21-40.

 

Congress abstracts and other publications

Jaenisch R; Tucker K; Beard C; Li E (1996)

DNA methylation and genomic imprinting.

Mol Biol Cell, 7(Suppl):8A

 

Tucker K L; Barde Y-A (1999)

Targeted expression of green fluorescent protein as a "living" neuron-specific marker.

Soc Neurosci Abst, 25(1-2):777

 

Tucker K L (2000)

Letter from the mouse house.

New England Review, 21:128-134.

 

Wernig M; Tucker KL; Gornik V; Scheffler B; Barde Y-A; Wiestler O D; Brüstle O (2001).

TAU-EGFP knock-in: a new tool for the selection and in vivo analysis of ES cell-derived neurons.

Acta Neuropathol, 102(5):546

 

Andorfer C; Kress Y; Espinoza M; de Silva R; Tucker K L; Barde Y-A; Duff K; Davies P (2001).

Characterization of a mouse line that expresses only the human isoforms of tau.

Soc Neurosci Abst, 27(1):1142

 

Lindemann L.; Schnuerch H.; Tucker K L; Barde Y-A (2001).
Testing A-Ephrins as regulators of axonal elongation and branching during development.

Soc Neurosci Abst, 27(1):1539

 

Malatesta P; Heins N; Tucker K L; Hack M; Chapouton P; Barde Y-A; Goetz M (2001).
Generation of neurons from glial cells: The role of Pax6.

Soc Neurosci Abst, 27(1):349

 

Tucker K L; Bradford C L; Barde Y-A (2002).

ENU mutagenesis of a GFP-expressing mouse strain to yield new mutations in peripheral nervous system development.

Soc Neurosci Abst, 27.24

 

Malatesta P; Heins N; Tucker K L; Hack M; Chapouton P; Barde Y-A; Goetz M (2002)

Generation of neurons from glial cells: The role of the transcription factor Pax6.

Devel Brain Res, 134 (1-2):A23-A24

 

Wernig M; Benninger F; Tucker KL; Barde Y-A; Wiestler O D; Beck H; Brüstle O (2002)
Characterization of ES cell-derived neurons after transplantation into the developing rat brain.

Acta Neuropathol, 104(5):576

 

Andorfer C; Kress Y; Espinoza M; de Silva R; Tucker K L; Barde Y-A; Duff K; Davies P (2002)

A mouse model of early tangle formation in the absense of mutations.

Neurobiol Aging, 23(1): S137

 

Wernig M; Benninger F O; Tucker K L; Gomik V; Wiestler O D; Barde Y-A; Beck H; Brüstle O (2002).

Lineage selection and in vivo analysis of ES cell-derived neurons.

Soc Neurosci Abst, 526.2

 

Benninger F; Beck H.; Wernig M.; Tucker K L; Brüstle O; Scheffler B (2003).

Functional integration of transplanted embryonic stem cell-derived neurons.

Neural Plasticity, 10(3):184

 

Wernig M; Benninger F; Tucker K L; Beck H; Brüstle O (2003).

Functional integration of transplanted ES cell-derived neurons.

Eur J Cell Biol, 82(S53):45

           

Willaredt M A; Hasenpusch-Theil K; Gardner H A R; Kitanovic I; Hirschfeld-Warneken V C; Gojak C P; Gorgas K; Bradford C L; Spatz J; Wölfl S; Theil T; Tucker K L (2009).

A crucial role for primary cilia in forebrain development.

Mech Dev, 126(Supplement 1):S262

 

Sanno H; Shen X; Kuru N; Bormuth I; Bobsin K; Gardner H; Komljenovic D; Tarabykin V; Erzurumlu R; Tucker K L (2010).

Rho GTPases control postnatal apoptosis and neuronal density in the cerebral cortex.

Int J Dev Neurosci, 8(SI):702

 

Weissmueller K; Scholl C; Wolfl S; Tucker K L (2010).

Analysis of histone deacetylase-mediated transcriptional control of forebrain neurogenesis via gene-array profiling.

Int J Dev Neurosci, 8(SI):684-685

 

Evsyukov V; Willaredt M A; Tucker K L (2010).

Positional cloning of cobblestone, a mouse mutant showing major defects in brain development, identifies Ift88 as a candidate gene.

Impulse, 7:1-14

 

 

Verantwortlich: E-Mail,   Letzte Änderung: Mon, 23.04.2018
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