224
E. C. Bailey et al.
modification, results in marked pattern abnormalities that are not detected with the full-length protein (Porter et al. 1996). Without the
cholesterol attachment, Hh-N diffuses farther and signals to cells that
are normally beyond its range.
Vertebrates appear to have used this feature to vary the concentration
of Shh-N during neural tube development. Shh is produced by the
notochord to induce adjacent floor plate cells in a contact-dependent
manner (Roelink et al. 1994) and at high concentrations (Roelink et al.
1995). The cholesterol attachment may anchor Shh-N to the notochord
surface and increase its local concentration. Later in neural tube development, Shh-N produced by the floor plate induces motor neurons at a
distance, but at lower protein concentrations (Roelink et al. 1995). How
Shh signals over longer distances is not well understood. If the protein
diffuses over many cell lengths, cleavage of the cholesterol tether might
be required. To date, no such enzyme or activity has been reported.
12.5.2 Modulation of Shh Signal Reception by Sterols
Sterols also appear to modulate the response of target cells to Hh family
members. Several lines of evidence suggest that inhibition of cholesterol
synthesis or homeostasis causes cyclopia in animals, remarkably similar to
that seen in Shh deficient mice. Exposure of pregnant ewes, mice, or
hamsters to cycloparnine, a plant alkaloid that resembles cholesterol, induces fetal cyclopia and other developmental abnormalities reminiscent of
Shh signaling defects (Keeler 1975; Keeler 1978). Patients with SmithLemli-Opitz Syndrome (SLOS), a human disorder with defects in delta
7 -sterol reductase, the terminal enzyme of cholesterol synthesis, also
manifest cyclopia as seen in individuals with HPE (Fitzky et al. 1998).
Recent studies have delimited what aspect of Shh signaling is disrupted by cyclopamine and inhibitors of distal cholesterol synthesis.
Studies using neural and stomach explants indicate that these agents
block the ability of target tissues to respond to Shh (Cooper et al. 1998;
Incardona et al. 1998; Kim and Melton 1998). This effect can be reversed in some cases by the addition of exogenous cholesterol (Incardona et al. 1998). The agents do not appear to block Shh cleavage or the
attachment of cholesterol (Cooper et al. 1998; Incardona et al. 1998).
Neither do these drugs exert their effects by inducing a general choles-
E. C. Bailey et al.
modification, results in marked pattern abnormalities that are not detected with the full-length protein (Porter et al. 1996). Without the
cholesterol attachment, Hh-N diffuses farther and signals to cells that
are normally beyond its range.
Vertebrates appear to have used this feature to vary the concentration
of Shh-N during neural tube development. Shh is produced by the
notochord to induce adjacent floor plate cells in a contact-dependent
manner (Roelink et al. 1994) and at high concentrations (Roelink et al.
1995). The cholesterol attachment may anchor Shh-N to the notochord
surface and increase its local concentration. Later in neural tube development, Shh-N produced by the floor plate induces motor neurons at a
distance, but at lower protein concentrations (Roelink et al. 1995). How
Shh signals over longer distances is not well understood. If the protein
diffuses over many cell lengths, cleavage of the cholesterol tether might
be required. To date, no such enzyme or activity has been reported.
12.5.2 Modulation of Shh Signal Reception by Sterols
Sterols also appear to modulate the response of target cells to Hh family
members. Several lines of evidence suggest that inhibition of cholesterol
synthesis or homeostasis causes cyclopia in animals, remarkably similar to
that seen in Shh deficient mice. Exposure of pregnant ewes, mice, or
hamsters to cycloparnine, a plant alkaloid that resembles cholesterol, induces fetal cyclopia and other developmental abnormalities reminiscent of
Shh signaling defects (Keeler 1975; Keeler 1978). Patients with SmithLemli-Opitz Syndrome (SLOS), a human disorder with defects in delta
7 -sterol reductase, the terminal enzyme of cholesterol synthesis, also
manifest cyclopia as seen in individuals with HPE (Fitzky et al. 1998).
Recent studies have delimited what aspect of Shh signaling is disrupted by cyclopamine and inhibitors of distal cholesterol synthesis.
Studies using neural and stomach explants indicate that these agents
block the ability of target tissues to respond to Shh (Cooper et al. 1998;
Incardona et al. 1998; Kim and Melton 1998). This effect can be reversed in some cases by the addition of exogenous cholesterol (Incardona et al. 1998). The agents do not appear to block Shh cleavage or the
attachment of cholesterol (Cooper et al. 1998; Incardona et al. 1998).
Neither do these drugs exert their effects by inducing a general choles-