My research program deals with questions at both ends of the developmental process. At the early end, we are striving to answer the multilevel question, “How do you build a cerebellum?”. At the later end, we are exploring the causes of the neuronal degeneration in several human diseases: Alzheimers and ataxia-telangectasia to name only two.

The early work focuses on what it means to be a Purkinje cell, the major large neuron of the cerebellar cortex. We study the role of the Engrailed-1 and Engrailed-2 genes, the orphan nuclear receptor RORa, and the tumor suppressor gene, retinoblastoma (Rb-1). Several lines of evidence suggest that, following migration to the cerebellar plate, young Purkinje cells require RB function to survive and in Rb-1 mutants, RORa is not expressed.

The genetic elements that act as cis-regulators of the Zebrin II/aldolase C gene form a bridge between the analysis of single cell identity and “group” identities. Analysis of transgenic mice suggests the existence of at least three regulatory elements: a basal glial cell-specific element, a Purkinje cell “enhancer”, and a striping element.

Taken together these approaches to early cerebellar developmental genetics offer a unique and comprehensive approach to the relationship between the genome and the brain. The neurodegeneration in Alzheimer’s Disease would seem a far distant problem from the regulation of early cerebellar development.

Yet, early experiments in mouse model systems have led to the hypothesis that many forms of neuronal cell death during are caused by a neuron unsuccessfully re-enterance into the cell cycle. Investigations in human material from Alzheimer’s Disease patients and non-demented, age-matched controls has revealed substantial immunocytochemical evidence for induction of several proteins normally found only in cycling cells.

We are actively exploring the trigger(s) that induce normally postmitotic neurons to re-express cell cycle proteins late in life as well as the molecular mechanism by which the induction of these proteins leads to cell death.

1. Yang Y, Varvel NH, Lamb BT, Herrup K. (2006)
   Ectopic cell cycle events link human Alzheimer’s disease and amyloid precursor protein transgenic mouse models. J Neurosci. 2006 Jan 18; 26(3):775-784.
   
2. Cicero S, Herrup K. (2005)
   Cyclin-dependent kinase 5 is essential for neuronal cell cycle arrest and differentiation. J Neurosci. 2005 Oct 19; 25(42):9658-9668.
   
3. Yang Y, Herrup K. (2005)
   Loss of neuronal cell cycle control in ataxia-telangiectasia: a unified disease mechanism. J Neurosci. 2005 Mar 9; 25(10):2522-2529.
   
4. Murcia CL, Gulden F, Herrup K. (2005)
   A question of balance: a proposal for new mouse models of autism. Int J Dev Neurosci. 2005 Apr-May; 23(2-3):265-275.
   
5. Romito-Digiacomo RR, Walther EU, Williams EA, Herrup K. (2005)
   Purkinje cell expression of the mouse aldolase C gene in transgenic mice is directed by an upstream regulatory element. Brain Res Mol Brain Res. 2005 Jan 5; 133(1):47-57.
   
6. Herrup K, Murcia C, Gulden F, Kuemerle B, Bilovocky N. (2005)
   The genetics of early cerebellar development: networks not pathways. Prog Brain Res. 2005; 148:21-27.
   
7. Herrup K, Neve R, Ackerman SL, Copani A. (2004)
   Divide and die: cell cycle events as triggers of nerve cell death. J Neurosci. 2004 Oct 20; 24(42):9232-9239.
   
8. Murcia CL, Bilovocky NA, Herrup K. (2004)
   Dissecting complex genetic interactions that influence the Engrailed-1 limb phenotype. Mamm Genome. 2004 May; 15(5):352-360.
   
9. Rivkin A, Herrup K. (2003)
   Development of cerebellar modules: extrinsic control of late-phase zebrin II pattern and the exploration of rat/mouse species differences. Mol Cell Neurosci. 2003 Dec; 24(4):887-901.
   
10. Bilovocky NA, Romito-DiGiacomo RR, Murcia CL, Maricich SM, Herrup K. (2003)
    Factors in the genetic background suppress the engrailed-1 cerebellar phenotype. J Neurosci. 2003 Jun 15; 23(12):5105-5112.
    
11. Yang Y, Mufson EJ, Herrup K. (2003)
    Neuronal cell death is preceded by cell cycle events at all stages of Alzheimer’s disease. J Neurosci. 2003 Apr 1; 23(7):2557-2563.
    
12. Herrup K, Arendt T. (2002)
    Re-expression of cell cycle proteins induces neuronal cell death during Alzheimer’s disease. J Alzheimers Dis. 2002 Jun; 4(3):243-247.
    
13. Gilmore EC, Herrup K. (2001)
    Neocortical cell migration: GABAergic neurons and cells in layers I and VI move in a cyclin-dependent kinase 5-independent manner. J Neurosci. 2001 Dec 15; 21(24):9690-9700.
    
14. Herrup K, Yang Y. (2001)
    Pictures in molecular medicine: contemplating Alzheimer’s disease as cancer: a loss of cell-cycle control. Trends Mol Med. 2001 Nov; 7(11):527.
    
15. Maricich SM, Gilmore EC, Herrup K. (2001)
    The role of tangential migration in the establishment of mammalian cortex. Neuron. 2001 Aug 2; 31(2):175-178.
    
16. Yang Y, Geldmacher DS, Herrup K. (2001)
    DNA replication precedes neuronal cell death in Alzheimer’s disease. J Neurosci. 2001 Apr 15; 21(8):2661-2668.
    
17. Liu T, Zwingman T, Li R, Pan T, Wong BS, Petersen RB, Gambetti P, Herrup K, Sy MS. (2001)
    Differential expression of cellular prion protein in mouse brain as detected with multiple anti-PrP monoclonal antibodies. Brain Res. 2001 Mar 30; 896(1-2):118-129.
    
18. Zwingman TA, Neumann PE, Noebels JL, Herrup K. (2001)
    Rocker is a new variant of the voltage-dependent calcium channel gene Cacna1a. J Neurosci. 2001 Feb 15; 21(4):1169-1178.
    
19. Wu Q, Combs C, Cannady SB, Geldmacher DS, Herrup K. (2000)
    Beta-amyloid activated microglia induce cell cycling and cell death in cultured cortical neurons. Neurobiol Aging. 2000 Nov-Dec; 21(6):797-806.
    
20. Gilmore EC, Herrup K, Nowakowski RS, Caviness VS Jr. (2000)
    Reply Trends Neurosci. 2000 Sep; 23(9):408-409.
    
21. Herrup K. (2000)
    Thoughts on the cerebellum as a model for cerebral cortical development and evolution. Novartis Found Symp. 2000; 228:15-24; discussion 24.
    
22. Gilmore EC, Herrup K. (2000)
    Cortical development: receiving reelin. Curr Biol. 2000 Feb 24; 10(4):R162-R166.
    
23. Gilmore EC, Nowakowski RS, Caviness VS Jr, Herrup K. (2000)
    Cell birth, cell death, cell diversity and DNA breaks: how do they all fit together? Trends Neurosci. 2000 Mar; 23(3):100-105.
    
24. Maricich SM, Herrup K. (1999)
    Pax-2 expression defines a subset of GABAergic interneurons and their precursors in the developing murine cerebellum. J Neurobiol. 1999 Nov 5; 41(2):281-294.
    
25. Gilmore EC, Ohshima T, Goffinet AM, Kulkarni AB, Herrup K. (1998)
    Cyclin-dependent kinase 5-deficient mice demonstrate novel developmental arrest in cerebral cortex. J Neurosci. 1998 Aug 15; 18(16):6370-6377.
    
26. Busser J, Geldmacher DS, Herrup K. (1998)
    Ectopic cell cycle proteins predict the sites of neuronal cell death in Alzheimer’s disease brain. J Neurosci. 1998 Apr 15; 18(8):2801-2807.
    
27. Kuemerle B, Zanjani H, Joyner A, Herrup K. (1997)
    Pattern deformities and cell loss in Engrailed-2 mutant mice suggest two separate patterning events during cerebellar development. J Neurosci. 1997 Oct 15; 17(20):7881-7889.
    
28. Maricich SM, Soha J, Trenkner E, Herrup K. (1997)
    Failed cell migration and death of purkinje cells and deep nuclear neurons in the weaver cerebellum. J Neurosci. 1997 May 15; 17(10):3675-3683.
    
29. Gilmore EC, Herrup K. (1997)
    Cortical development: layers of complexity. Curr Biol. 1997 Apr 1; 7(4):R231-R234.
    
30. Yang X, Yang F, Fyodorov D, Wang F, McDonough J, Herrup K, Deneris E. (1997)
    Elements between the protein-coding regions of the adjacent beta 4 and alpha 3 acetylcholine receptor genes direct neuron-specific expression in the central nervous system. J Neurobiol. 1997 Mar; 32(3):311-324.
    
31. Herrup K, Kuemerle B. (1997)
    The compartmentalization of the cerebellum. Annu Rev Neurosci. 1997; 20:61-90.
    
32. Herrup K, Shojaeian-Zanjani H, Panzini L, Sunter K, Mariani J. (1996)
    The numerical matching of source and target populations in the CNS: the inferior olive to Purkinje cell projection. Brain Res Dev Brain Res. 1996 Oct 23; 96(1-2):28-35.
    
33. Herrup K. (1996)
    The weaver mouse: a most cantankerous rodent. Proc Natl Acad Sci U S A. 1996 Oct 1; 93(20):10541-10542.
    
34. Herrup K, Busser JC. (1995)
    The induction of multiple cell cycle events precedes target-related neuronal death. Development. 1995 Aug; 121(8):2385-2395.
    
35. Threadgill DW, Dlugosz AA, Hansen LA, Tennenbaum T, Lichti U, Yee D, LaMantia C, Mourton T, Herrup K, Harris RC, et al.. (1995)
    Targeted disruption of mouse EGF receptor: effect of genetic background on mutant phenotype. Science. 1995 Jul 14; 269(5221):230-234.
    
36. Herrup K, Silver J. (1994)
    Cortical development and topographic maps: patterns of cell dispersion in developing cerebral cortex. Curr Opin Neurobiol. 1994 Feb; 4(1):108-111.