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Neuronal migration and circadian rhythms
Several projects have recently emerged in the laboratory, partly in collaborations with
other investigators.
- Mechanisms of neuronal migration in the mammalian brain
We have been interested for some time in the mechanism of human diseases caused by neuronal migration defects. An example is
Miller-Dieker Syndrome (MDS), which is characterized by a mislayering of the cerebral cortex, because neurons have migrated to inappropriate
positions. Such migration defects and the resulting cortical abnormalities are thought to contribute to various diseases of the brain
including schizophrenia. We have shown that the MDS gene product (LIS1) physically interacts with several other
proteins whose function we currently investigate by generating and analyzing the corresponding mouse mutations using gene
targeting. In collaboration with Dr. Li-Yuan Yu-Lee (Molecular & Cell Biology, BCM) we recently discovered that LIS1
protein interacts with NudC, a protein implicated in the organization of the cytoskeleton. There are several other mouse mutations that
have cortical defects and one of our aims is to determine whether and how the corresponding gene products interact and how this contributes
to neuronal migration.
- Genetic basis of circadian rhythms
The fortuitous discovery of putative circadian genes in mammals (per genes) has prompted us to become interested in this area
of research. The biology of circadian rhythms constitutes a relatively little investigated and
certainly not well understood problem in which molecular mechanism of signal transduction and behavior can be integrated. In mammals, the
circadian clock resides in the suprachiasmatic nucleus (SCN), a small group on neurons that express the mammalian per genes in a circadian
pattern. The questions we are addressing concern the regulation of the genes as well as the nature of the genes they regulate. The body
harbors a so-called "circadian clock" by which it measures a 24-hour rhythm. In collaboration with Dr. Cheng Chi Lee
(Molecular and Human Genetics, BCM), we were able to identify three genes that regulate the circadian clock. When these genes are examined in
mice, we find that their temporal expression pattern in the SCN follows a 24-hour rhythm. We have analyzed mice with mutations in the mper2 gene and find that they have lost their
clock mechanism. We now plan to analyze the same genes in humans and hope to find out whether people with abnormal sleep-wake patterns
have mutations in the mper2 gene.
- Generation of a gene expression database for the mouse brain
We are in the process of developing high-throughput methods to analyze gene expression patterns in the mouse brain using in situ
hybridization (HITISH). We chose the brain because elucidation of its development and function is a major topic of biological research now
and in the 21st century. In collaboration with Dr. Wah Chiu (Biochemistry & Molecular Biology, BCM), we are also
developing imaging software that will allow us to generate a database of gene expression patterns in the adult mouse brain. The types of
genes that we will be studying will primarily be signal transduction components disrupted in the so-called "Omnibank", a collection of
mouse ES cells (generated by Lexicon Genetics, Houston, TX). Each ES cell carries a tag inserted into a particular mouse gene thereby
disrupting this gene. These ES cells can be used to generate the corresponding knock-out mouse and thus the HITISH project integrates
with other important efforts in mammalian genomics. Moreover, knowing gene expression patterns allows one to eventually create a gene
activity map of the brain.
Selected Publications
Albrecht U, Sun Z, Eichele G, Lee CC (1997) A differential response of two putative mammalian
circadian regulators, mper1 and mper2, to light. Cell 91:1055-1064.
Morris SM, Albrecht U, Reiner O, Eichele G, Yu-Lee, L-Y (1998) The lissencephaly gene product Lis1, a
protein involved in neuronal migration, interacts with nuclear movement protein NudC. Current Biology 8:603-
606.
Zheng B, Larkin DW, Albrecht U, Sun ZS, Sage M, Eichele G, Lee CC, Bradley A (1999) The mPer2 gene
encodes a functional component of the mammalian circadian clock. Nature 400:169-173.
Zheng B, Albrecht U, Kaasik K, Sage M, Lu W, Vaishnav S, Li Q, Sun ZS, Eichele G, Bradley A,
Lee CC (2001) Nonredundant roles of the mPer1 and mPer2 genes in the mammalian circadian clock. Cell
105:683-694.
Lu HC, Swindell EC, Sierralta WD, Eichele G, Thaller C (2001) Evidence for a role of protein kinase C in FGF
signal transduction in the developing chick limb bud. Development 128:2451-2460.
Carson JP, Thaller C, Eichele G (2002) A transcriptome atlas of the mouse brain at cellular resolution.
Current Opinion in Neurobiology 12:562-565.
Reymond A, Marigo V, Yaylaoglu MB, Leoni A, Ucla C, Scamuffa N, Caccioppoli C, Dermitzakis ET, Lyle R, Banfi S,
Eichele G, Antonarakis SE, Ballabio A (2002) Human chromosome 21 gene expression atlas in the mouse. Nature
420:582-586.
Albrecht U, Eichele G (2003) The mammalian circadian clock. Current Opinion in Genetics and Development
13:271-277.
Moeller C, Swindell EC, Kispert A, Eichele G (2003) Carboxypeptidase Z (CPZ) modulates Wnt signaling and
regulates the development of skeletal elements in the chicken. Development 130:5103-5111.
Contact Information
- Gregor Eichele, Ph.D.
- Department of Biochemistry and Molecular Biology
- Baylor College of Medicine
- One Baylor Plaza S303
- Houston, Texas 77030, U.S.A.
- Tel: (713) 798-3718
- Fax: (713) 798-3203
- E-mail: geichele@bcm.tmc.edu
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