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Department of Molecular Genetics, UT Southwestern, Dallas, TX 75235 and a Gladstone Institute of Cardiovascular Disease and b Department of Medicine, University of California, San Francisco, CA 94141–9100
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ABSTRACT |
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 TOP ABSTRACT INTRODUCTIONREFERENCES |
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KEY WORDS: • LRP • exencephaly • central nervous system • hedgehog • scavenger receptor class B type I
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INTRODUCTION |
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TOPABSTRACTINTRODUCTIONREFERENCES |
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,
Smithies 1993
) has led to the identification of an increasing number of
genes with important functions during embryonic development. These also
include several genes that are involved in various aspects of
cholesterol metabolism in particular or lipid metabolism in general.
They can be classified into three groups of genes involved in the
following activities: 1) cholesterol biosynthesis,
2) lipid transport and lipoprotein assembly and
3) receptors that mediate the cellular uptake of lipids and
cholesterol. Defects in these genes frequently affect the formation or
the function of the nervous system, which seems to be critically
dependent on an unimpaired supply of cholesterol, especially during the
early stages of development (Farese and Herz 1998
).
The developing embryo can obtain the cholesterol it so critically
requires for its development by two pathways, endogenous biosynthesis
or lipoprotein/receptor–mediated uptake. Genetically defective or
pharmacologically inhibited enzymes that are involved in cholesterol
biosynthesis have been shown to or are suspected to give rise to
developmental or postnatal abnormalities include the following:
ß-hydroxyl-ß-methyl glutaryl
(HMG)4-CoA reductase, mevalonate kinase,
7-reductase and 24-reductase.
The last-mentioned two enzymes catalyze the ultimate steps in cellular
cholesterol biosynthesis. In a severe genetic disorder,
Smith-Lemli-Opitz Syndrome (SLO), 7-reductase, in particular, is
defective (Tint et al. 1994
). A phenotype similar to SLO was seen in
some cases in which 7-reductase activity was normal, but
24-reductase activity in the tissues examined was reduced. A genetic
deficiency of 7-reductase in animals has not been reported, but the
recent cloning of the mammalian enzyme will allow the generation of an
animal model for SLO by gene targeting in mice. Pharmacologic
inhibition of 7-reductase with the inhibitor AY9944 in rats,
however, has defined the critical window during development between E6
and E10. Feeding of a high cholesterol diet prevented this teratogenic
effect (Roux et al. 1979
).
The mutated proteins involved in lipoprotein transport and assembly
that give rise to developmental abnormalities (in the mouse) or
postnatally affect the function of the nervous system of afflicted
humans are apolipoprotein (apo) B and the microsomal transfer protein
(MTP). Although both genes appear to be absolutely required for the
normal development of the central nervous system in the mouse, this is
not the case in humans. In rodents, however, apoB and MTP seem to be
necessary for the lipoprotein-mediated transport of lipids (Farese et
al. 1995
, Raabe et al. 1998
) and the neuro-essential lipophilic vitamin
E (tocopherol) (Verma and King 1967
) to nervous tissues. Several
mutations that affect embryonic development in mice with different
severity have been introduced into the apoB gene. A complete knockout
of the apoB gene leads to embryonic demise at a very early stage
(before d 9.5 postconception). In these embryos, development of
neuroectoderm-derived tissues, probably including the neural crest, is
severely impaired. Other mutations that only partially inactivate the
gene or reduce its functional expression have intermediate phenotypes
that vary from severe forms of exencephaly to the development of
hydrocephalus during adulthood (Farese et al. 1992
, 1995
, 1996a
and
1996b
, Homanics et al. 1993
and 1995
, Huang et al. 1995
). Mutations in
apoB preferentially affect the development of posterior parts of the
developing central nervous system, in particular the alar plate. This
is in contrast to the phenotypes observed in rats in which
7-reductase was pharmacologically inhibited by feeding AY9944 to
pregnant females. There, inhibition of the final step of endogenous
cholesterol biosynthesis affected mainly the formation of rostral
(forebrain-derived) structures (Roux et al. 1980
).
The role of MTP in the embryonic development of the mouse remains under
investigation. Recent results showed that the gene is indeed required
for embryonic viability because most MTP-knockout embryos died at
mid-gestation; the few that survived past this time point had
neurodevelopmental abnormalities similar to those of apoB gene knockout
mice (Raabe et al. 1998
).
The third group of genes that participate in cholesterol uptake by the
embryo and that affect embryonic survival and/or development of the
nervous system comprises several of the presently known lipoprotein
receptors that mediate the cellular uptake or exchange of cholesterol.
Knockout of the HDL receptor SR-BI (scavenger receptor class B type I)
in mice suggests that SR-BI–deficient embryos survive to term at a
reduced rate (Rigotti et al. 1997
). Two members of the LDL receptor
gene family, the LDL receptor–related protein (LRP) and megalin, are
multifunctional endocytic receptors that can mediate the cellular
uptake of apoB- and apoE-containing lipoproteins (Farese and Herz 1998
). A complete knockout of the LRP gene results in early embryonic
lethality that also severely affects the formation of the central
nervous system (Herz et al. 1992
). However, the resulting embryos are
generally grossly malformed, suggesting more pleiotropic mechanisms.
Megalin-deficient mouse embryos, in contrast to LRP-deficient embryos,
develop to term. A defect of the megalin gene selectively affects the
development of the forebrain, resulting in a phenotype that is very
similar to that seen in SLO (Willnow et al. 1996
). Nevertheless, the
interpretation of the phenotypes of LRP- and megalin-deficient embryos
is complicated by the fact that both receptors are multifunctional.
They bind and endocytose not only lipoproteins, but also a range of
other ligands, including proteases, protease inhibitors and protein
carriers of vitamins, e.g., vitamin D–binding protein (A. Nykjaer and
T.E. Willnow, personal communication) and vitamin B-12–binding protein
(Moestrup et al. 1996
).
At what stage during the transport of cholesterol and lipids from the
mother to the embryonic target tissues are MTP, apoB and the
lipoprotein receptors required? Lipids transported from the maternal
circulation to the embryo have to cross the maternal-fetal interface.
At the critical early stages of development, it is mainly the yolk sac
membrane that shields the embryo from direct access to lipoproteins
circulating in the maternal bloodstream. All components that are
transported within these particles must first be unloaded on the apical
side of the yolk sac before they are repackaged and resecreted on the
embryonic side of the membrane. From there, they gain access to the
exposed neuroepithelial surface. This form of transport of nutrients to
the embryo is particularly important before the neural tube closes and
before a functional circulatory system has been established in the
embryo, at which stage the placenta becomes mainly responsible for
nutritional supply. On the apical surface of the yolk sac epithelium, a
battery of lipoprotein receptors, including all known members of the
LDL receptor gene family as well as SR-BI (also called the HDL
receptor), mediate the uptake of various lipoprotein particles and
content lipids (Farese and Herz 1998
). Within the yolk sac, MTP and
apoB are required to repackage these lipids (mostly triacylglycerols)
into lipoproteins. In the absence of apoB or MTP, cytosolic lipid
droplets accumulate in the visceral yolk sac endodermal cells (Farese
et al. 1996
, Raabe et al. 1998
).
The requirement for receptors at two stages of lipid transport into the embryo makes it difficult to unequivocally determine the critical step(s) at which they are required. Does a defect of LRP or megalin manifest itself on the yolk sac surface by a deficiency in the selective uptake of a lipoprotein particle on that surface or on the embryonic target tissue (e.g., the neuroepithelium)? Tissue-specific gene knockout approaches are currently under development to address these functionally important questions.
Why is the unimpaired supply of cholesterol to the developing embryo so
important and why does it affect primarily the development of the
central nervous system? Although it is not possible to give a complete
answer to these questions at present, a possible picture is starting to
emerge. The central nervous system undergoes an enormous cellular
expansion at this critical time of embryonic development. Cholesterol
is a crucial component of the plasma membranes of all cells, and the
proper ratio of cholesterol and phospholipids determines their
physicochemical characteristics. Thus, it is conceivable that during
evolution a checkpoint was established that determines whether
sufficient cholesterol is available to proceed with the expansion of
the developing brain or whether cell division should slow down. The
recent discovery of the cholesterol-mediated activation of the hedgehog
protein family of signaling molecules (Porter et al. 1996
) and
demonstration that sonic hedgehog is required for the development of
the mouse brain (Chiang et al. 1996
) support this hypothesis and
suggest that hedgehog proteins may be involved in the control of this
checkpoint.
As we continue to employ new and powerful molecular genetic approaches to refine our analysis of the genes that participate in the regulation of cholesterol biosynthesis, transport and metabolism, we will gain a deeper understanding of how this Janus-faced sterol determines our development during these early stages of our lives.
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FOOTNOTES |
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1 Presented at the symposium "Assembly and
Physiology of Apolipoprotein B-Containing Lipoproteins It's Not Just
for Heart Disease Anymore!" as part of Experimental Biology 98, April
18–22, 1998, San Francisco, CA. The symposium was sponsored by the
Energy and Macronutrient Research Interest Section of the American
Society for Nutritional Sciences, the Egg Nutrition Center, the
American Heart Association-Western States Affiliate, Merck Research
Laboratories, Bristol-Meyers Squibb Pharmaceutical Research Institute
and Parke-Davis Pharmaceutical Research. Published as a supplement to
The Journal of Nutrition. Guest editors for this supplement
were Rosemary L. Walzem, University of California, Davis, and Robert L.
Hamilton, University of California, San Francisco, CA.
2 Supported by grants from the National
Institiutes of Health (HL20948) and the Keck Foundation. J. H. is
an Established Investigator of the American Heart Association and
Parke-Davis.
3 Abbreviations used: apo, apolipoprotein; LRP,
LDL receptor–related protein; MTP, microsomal transfer protein; SLO,
Smith-Lemli-Opitz Syndrome; SR-BI, scavenger receptor class B type I.
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