The generation of neurons from stem and progenitor cells is a
complex, tightly regulated process known as neurogenesis. Researchers from Ludwig-Maximilians-Universitaet (LMU) in Munich have
demonstrated how deregulation of an epigenetic mechanism that is active
only in the early phases of neurogenesis triggers the subsequent death
of neural cells.
led by Professor Dr. Magdalena Götz, Chair of Physiological Genomics at
LMU and Director of the Institute for Stem Cell Research at the
Helmholtz Zentrum München, have shown in collaboration with Professor
Dr. Gunnar Schotta, Biomedical Center LMU, that epigenetic mechanisms
which are brought into play at an early stage of neurogenesis, have an
important impact on the subsequent fate of neurons.
‘How deregulation of an epigenetic mechanism that is active only in the early phases of neurogenesis triggers the subsequent death of neural cells has been demonstrated by scientists.’
These new findings
appear in Genes and Development
, a leading journal in the field of developmental biology.
In order to elucidate the significance of early epigenetic
modifications on the development of neural cells during embryogenesis in
the mouse, Götz and her colleagues specifically inactivated the gene
Uhrf1. This gene is known to control a number of epigenetic functions,
including DNA methylation, and is active from very early stages of
neurogenesis. The methylation of specific nucleotide bases in DNA often
serves to switch genes off.
Conditional knockout of Uhrf1, in a region of the forebrain, led to
the activation of endogenous retroviral elements (ERV) in the genome,
which are otherwise silenced by methylation. Further investigation
revealed that members of the Tet family of enzymes are largely mediating
the demethylation of the ERVs, thus appearing be functionally activated
in the absence of Uhrf1.
Moreover, these ERVs remained active not only
in later stages of embryogenesis but also into postnatal stages,
suggesting that their activation is non-reversible. The aberrant and
ongoing activation of ERVs caused an accumulation of retroviral proteins
in the affected cells and deregulation of genes and pathways. This in
turn led to the progressive disruption of vital cellular processes and
ultimately precipitated a massive wave of cell death.
"Our results reveal that certain key factors - such as the gene
Uhrf1 - that are transiently activated only in early neurogenesis can
have a crucial impact on cell fate, which may only manifest weeks
later," says Götz. "Our model system provides us with fascinating
insights into these mechanisms, which are also of great interest in the
context of neurodegenerative diseases."