Beyond these x linked abnormalities there are at

Beyond these X-linked abnormalities, there are at least two genetic disor-
ders that compromise the nervous system generated by single gene muta-
tions in homeobox-like transcription factors. Aniridia (characterized by loss
Early Brain Development
515
tion of cranial nerves in the developing
brain. Mutation or ectopic activation of
Hox genes in mice alters the position of
specific cranial nerves, or prevents their
formation. Mutation of the HoxA-1 gene
by homologous recombination—the so-
called “knockout” strategy for targeting
mutations to specific genes—prevents
normal formation of rhombomeres. In
these animals, development of the exter-
nal, middle, and inner ear is also com-
promised, and cranial nerve ganglia are
fused and located incorrectly. Con-
versely, when the HoxA-1 gene is
expressed in a rhombomere where it is
usually not seen, the ectopic expression
causes changes in rhombomere identity
and subsequent differentiation. It is
likely that problems in rhombomere for-
mation are the underlying cause of con-
genital nervous system defects involv-
ing cranial nerves, ganglia, and
peripheral structures derived from the
cranial neural crest (the part of the
neural crest that arises from the hind-
brain).
The exact relationship between early
patterns of rhombomere-specific gene
transcription and subsequent cranial
nerve development remains a puzzle.
Nevertheless, the correspondence
between these repeating units in the
embryonic brain and similar iterated
units in the development of the insect
body (see Figure 21.5) suggests that dif-
ferential expression of transcription fac-
tors in specific regions is essential for the
normal development of many species. In
a wide variety of animals, spatially and
temporally distinct patterns of transcrip-
tion factor expression coincide with spa-
tially and temporally distinct patterns of
differentiation, including the differentia-
tion of the nervous system. The idea that
the bulges and folds in the neural tube
are segments defined by patterns of gene
expression provides an attractive frame-
work for understanding the molecular
basis of pattern formation in the develop-
ing vertebrate brain.
References
C
ARPENTER
, E. M., J. M. G
ODDARD
, O. C
HISA
-
KA
, N. R. M
ANLEY AND
M. C
APECCHI
(1993)
Loss of HoxA-1 ( Hox-1.6 ) function results in
the reorganization of the murine hindbrain.
Development 118: 1063–1075.
G
UTHRIE
, S. (1996) Patterning the hindbrain.
Curr. Opin. Neurobiol. 6: 41–48.
L
UMSDEN
, A.
AND
R. K
EYNES
(1989) Segmental
patterns of neuronal development in the
chick hindbrain. Nature 337: 424–428.
V
ON
K
UPFFER
, K. (1906) Die morphogenie des
central nerven systems. In Handbuch der ver-
gleichende und experiementelle Entwick-
lungslehreder Wirbeltiere , Vol. 2, 3: 1–272. Fis-
cher Verlag, Jena.
W
ILKINSON
, D. G.
AND
R. K
RUMLAUF
(1990)
Molecular approaches to the segmentation of
the hindbrain. TINS 13: 335–339.
Z
HANG
, M.