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SPECIFICATION OF LEFT-RIGHT POLARITY 
Paul A. Overbeek, Ph.D., M.B.A., Assistant Investigator 
During mammalian development an initially sym- 
metrical embryo proceeds to establish dorsal- 
ventral, anterior-posterior, and left-right polarities. 
Left-right asymmetries are late-appearing and are 
most apparent in the visceral organs such as stom- 
ach, spleen, liver, and heart. The molecular mecha- 
nisms that specify mammalian embryonic axes re- 
main to be elucidated. Recently a transgenic family 
of mice that has an insertional mutation causing a 
reversal of embryonic left-right polarity was identi- 
fied. Initial characterization of this new mutation 
has been pursued over the past year. 
The mutation was identified in the transgenic fam- 
ily OVE2 10, which was generated by microinjection 
of a tyrosinase minigene into one-cell embryos of 
the albino mouse strain FVB/N. The albinism of non- 
transgenic FVB mice is due to a point mutation in the 
gene encoding tyrosinase, the first enzyme in the 
pathway to melanin synthesis. Introduction of a 
functional tyrosinase minigene into the FVB genome 
results in gene cure and restoration of the ability to 
synthesize melanin. Transgenic mice become pig- 
mented and can be identified by simple visual in- 
spection. In family OVE210 the transgenic mice 
have light brown fur and darkly pigmented eyes. 
They have a single site of integration with duplicate 
head-to-tail copies of the tyrosinase minigene. 
When OVE210 mice were inbred, all of the ho- 
mozygotes were found to have a reversal of their 
visceral left-right polarity. All of the major internal 
organs, including heart, lungs, stomach, spleen, and 
pancreas, were located on the side of the body op- 
posite their normal position. This condition also oc- 
curs occasionally in humans and is referred to as 
situs inversus. 
The inbred mice, in addition to the situs inver- 
sus, develop severe jaundice within 24 hours after 
birth. Serum bilirubin levels are elevated 20-fold. 
The mice suckle normally but show a marked failure 
to thrive, typically dying 3-7 days after birth, gener- 
ally at their birth weight. Examination of the vis- 
ceral organs by histology revealed that the situs in- 
versus mutants suffer from severe kidney pathology, 
with defective glomeruli and distended renal tu- 
bules. 
Situs inversus in humans is often associated with 
structural defects in the dynein arms of the cilia (a 
condition termed Kartagener's syndrome). The 
situs inversus transgenic mutants were checked for 
ciliary defects. Ciliated tracheae were collected and 
244 
