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CONTROL OF GENE EXPRESSION IN THE MAMMALIAN CEREBELLUM 
AND DURING THE CELL CYCLE 
Nathaniel Heintz, Ph.D., Investigator 
The studies in Dr. Heintz's laboratory focus on the 
identification of molecular mechanisms controlling 
gene expression in the developing cerebellum and 
during the cell cycle. The elucidation of these mech- 
anisms should provide fundamental insights into the 
biological transitions that underlie the development 
of the mammalian central nervous system and the 
control of cell division. 
Molecular Approaches to Understanding 
Development of the Mammalian Cerebellum 
The mammalian cerebellum is a complex and 
highly stereotyped structure in which major pattern 
formation and functional organization occur post- 
natally. It is therefore amenable to study, and its 
development has been described in detail at the his- 
tological level. An extensive literature has docu- 
mented the importance of cell-cell interactions in 
the generation and maintenance of normal cerebel- 
lar architecture. Furthermore, there are at least 
eight recessive mutations in inbred mouse strains 
that perturb cerebellar structure and function. 
Dr. Heintz's laboratory has initiated several ap- 
proaches toward identification of genes that are ei- 
ther required for — or respond to — specific transi- 
tions that occur during the development of the 
mammalian cerebellum. To identify genes impor- 
tant for the normal function of the cerebellum, the 
laboratory has initiated molecular genetic ap- 
proaches to isolate several genes responsible for in- 
herited neurologic disorders of the mouse. Signifi- 
cant progress has been made toward identifying the 
genes responsible for the lurcher (Lc) and mean- 
dertail (mea) mutant genes. 
The well-studied semidominant Lc mutation re- 
sults in degeneration and death of essentially all cer- 
ebellar Purkinje cells, commencing ~10 days after 
birth. Recent light and electron microscopic stud- 
ies, combined with in situ hybridization experi- 
ments, have strongly suggested that Lc Purkinje cells 
die by the process of apoptosis. Identification of the 
Lc mutation should provide fundamental insights 
into the molecular events that can ectopically acti- 
vate programmed cell death in inherited neurode- 
generative diseases. Genetic mapping studies have 
identified two molecular markers that flank the Lc 
gene by ~0.5 cM. One marker has been used to 
screen a yeast artificial chromosome (YAC) mouse 
genomic library prepared by Dr. Shirley Tilghman's 
laboratory (HHMI, Princeton University) to identify 
a 280-kb YAC clone containing mouse genomic 
DNA near the Lc locus. This resource and correlation 
of the physical and genetic maps will allow an ori- 
ented genomic walk toward the Lc gene. 
A similar approach is under way to isolate the mea 
gene, an intriguing recessive mutation that results in 
skeletal abnormalities in the tail and cerebellar ab- 
normalities. In collaboration with Drs. Mary Beth 
Hatten and Carol Mason (Columbia University Col- 
lege of Physicians and Surgeons), Dr. Heintz's labo- 
ratory has discovered that the mea gene influences 
compartmental organization in the mammalian 
brain. Three-dimensional reconstructions of the 
mea cerebellum have established that this mutation 
results in deletion of a specific quadrant of the 
mouse cerebellum. A molecular probe mapping 
~0.5 cM from the mea gene has been identified. 
Genetic analysis of two additional neurologic mu- 
tants, tottering (tg) and nervous (nr), is also under 
way. The eventual cloning of these and other genes 
identified by mouse neurological mutations will 
provide important insights into the development of 
the mammalian brain. 
A variety of subtractive cloning techniques have 
also been employed to isolate a large number of 
cDNA clones for mRNAs that are cell specific or de- 
velopmentally regulated during cerebellar develop- 
ment. These clones are now being analyzed to de- 
cide which are specific markers for developmental 
transitions that occur during the formation of the 
cerebellum. During the past year, in situ hybridiza- 
tion studies have established that specific stages in 
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