Biomedical Engineering Reference
In-Depth Information
1. VANGL PROTEINS, NEURULATION, AND NEURAL
TUBE DEFECTS
Neurulation, the process by which the brain and spinal cord form dur-
ing embryonic development, culminates in the formation of the primordial
structure of the central nervous system, the neural tube (NT). Aberrations in
the formation of the NT result in neural tube defects (NTDs) such as spina
bifida and anencephaly, conditions in which the central canal of the mal-
formed brain or spinal cord remains open to the environment. Spina bifida
and anencephaly are very frequent in humans (1/1000 live births) and are
second only to congenital heart defects as a cause of perinatal mortality.
The cellular and molecular mechanisms contributing to neurulation are
largely unknown, and multiple factors, both genetic and environmental,
have been implicated in the etiology of NTDs underlying their causal het-
erogeneity ( Greene, Stanier, & Copp, 2009; Kibar, Capra, & Gros, 2007 ).
The mouse is an excellent model to study the formation of NT because
of the accessibility of the developing embryo, the abundance of mutants
affecting neurulation, and the ease to manipulate environmental and genetic
influences on this process ( Harris & Juriloff, 2010; Wallingford, 2005 ). In
mice, NT closure is initiated at specific “closure sites” and failure of
closure at any of these sites leads to the various NTDs ( Fig. 10.1 ). Failure
of closure I results in the most severe NTD, craniorachischisis, when the
NT remains completely open from midbrain-hindbrain junction to the
tail end. Failure of the caudal spread of fusion from closure site I causes
spina bifida, whereas distortion of closure at sites II and III leads to rostral
NTD, anencephaly ( Copp & Greene, 2010 ; Fig. 10.1 ). The identification
and characterization of mutations causing NTDs in mice provide an entry
point not only for studying the role of these genes, proteins, and cellular
mechanisms of neurulation but also for identifying genes involved in the
pathogenesis of NTDs in humans.
A large number of mouse mutants harboring different types of NTDs
have been described over the years ( Harris & Juriloff, 2010 ). Among them,
Loop-tail ( Lp ) is a semidominant mutation on chromosome 1 originally
described by Strong in 1949 ( Strong &Hollander, 1949 ). The Lp/ þ hetero-
zygotes display a characteristic “looped” or severely kinked tail ( Fig. 10.2 )
and show wobbly head movements ( Strong &Hollander, 1949 ). The Lp/Lp
homozygotes die in utero of a severe NTD, craniorachischisis, that arises from
a failure to initiate closure at the closure site I, and NT remains completely
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