MDC Researchers Reveal Molecular Mechanism Underlying Severe Anomalies of the Forebrain
Cholesterol
has a bad reputation because it may lead to vascular calcification in adults
(atherosclerosis) as well as to heart attacks and strokes. However, cholesterol
is vital for embryonic development because it controls the development of the
central nervous system. The lack of it can lead to severe developmental
disorders of the forebrain (prosencephalon), the
largest region of the human brain. One in 250 pregnancies does not come to term
due to this malformation called holoprosencephaly
(HPE). One in 16000 children is born with HPE, of which the mildest form is cleft
lip and palate. In severe forms of HPE the affected children do not survive the
first weeks of life.
HPE may be
due to genetic factors, but environmental factors such as viral infections or alcohol
abuse during pregnancy may also cause the malformation. Moreover, the
cholesterol metabolism is also frequently disturbed. Thus, patients whose
bodies cannot produce cholesterol due to a genetic disorder inevitably have HPE.
As
Professor Willnow explained, the human brain develops from the neural tube, a
simple tube-like cluster of cells in the embryo. Why defects in cholesterol
metabolism lead to a developmental disorder of the neural tube and to HPE is
thus far not completely understood. The studies of the Berlin researchers may
give a possible clue. They identified a receptor called LRP2 that is formed in
the neural tube and can bind lipoproteins, which are the transport form of
cholesterol.
Interestingly,
this receptor also binds an important signal molecule of forebrain development
(sonic hedgehog, abbreviated SHH). As the researchers demonstrated, this
lipoprotein receptor drives the accumulation of SHH in the neural tube at a specific
site and induces the development of the forebrain structures. The researchers now
suspect that cholesterol – directly or indirectly – plays a central role in
controlling the activity of this novel receptor and assume that disturbances in
cholesterol metabolism lead to a loss of function of this auxiliary receptor for
SHH signaling.
*LRP2 Is an Auxiliary SHH Receptor Required to Condition the Forebrain
Ventral Midline for Inductive Signals
Annabel Christ1, Anna Christa1, Esther
Kur1, Oleg
Lioubinski1, Sebastian Bachmann2, Thomas E. Willnow1,3* and
Annette Hammes1,3
1Max Delbrück Center for Molecular Medicine
2Institute
for Vegetative Anatomy Charité Universitätsmedizin,
D-13125 Berlin, Germany
3These
authors contributed equally to this work
The dashed line marks the region of the neural tube out of which the forebrain develops. There in mouse embryos, a binding site (lipoprotein receptor LRP2) (green) for cholesterol is normally found (left image). This binding site plays a key role in the development of the forebrain. The signaling molecule sonic hedgehog (SHH) (red) arises from the structure marked with the arrow below the neural tube (prechordal plate) and accumulates in the overlying neural tube. Therefore a red signal is also visible in the forebrain structure. In mouse embryos in which the gene encoding LRP2 has been inactivated (right image), SHH is produced in the prechordal plate (arrow), but the signaling molecule does not accumulate in the overlying marked forebrain structure. The LRP2 receptor is lacking (no green signal). The researchers conclude that not only cholesterol is important for the activation and distribution of the signaling molecule SHH, but that also a lipoprotein receptor LRP2 is required in the target field to enhance the signal molecule. (Photo: Annabel Christ/ Copyright: MDC)
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