Cell and Molecular Biology of DNA Methyltransferase 1 - International Review of Cell and Molecular Biology - page 25

4.5. DNMT1 and development
The rapid increase in CpG methylation soon after embryo implantation into
the uterine wall suggests that much of postimplantation embryogenesis pro-
ceeds in the presence of widespread genome maintenance methylation.
Maintenance of imprinted DMDmethylation precedes implantation, during
preimplantation, and continues on as more of the genome is subject to main-
tenance methylation. Thus, we would expect that postimplantation devel-
opment is heavily dependent on DNMT1 function. This dependence is
evident from the results of multiple experiments showing the effects of
decreasing or increasing DNMT1 activities. In this section, we will describe
some of the key observations in this regard.
In epidermal tissue, the progenitor cells express higher levels of DNMT1
and the differentiating cells have very low or undetectable DNMT1 protein.
Depletion of DNMT1 in epidermal tissues led to premature differentiation
and exit from the progenitor cell compartment and tissue loss. Differentia-
tion has been shown to be associated with downregulation of DNMT1 and
demethylation and expression of epidermal differentiation genes. UHRF1
has also been shown to be essential for suppression of premature differenti-
ation and sustained proliferation. Contrastingly, demethylation-promoting
genes like GAD45A (see Section 5.2 ) promote induction of genes mediating
epidermal differentiation ( Sen et al., 2010 ).
A retinal-specific Dnmt1 deletion that does not express DNMT1 from
the onset of neurogenesis shows continuous proliferation of neuronal pro-
genitor cells with an increased number of cells in G1 phase. The postmitotic
neurons show defective differentiation, ectopic cell soma, and aberrant den-
dritic morphologies. The rhodopsin-expressing cells are mislocalized and
undergo cell death, much the same as other types of neurons in postnatal
retina. These results indicate that DNMT1 is critical for expansion of the
retinal progenitor pool and for maturation and survival of postmitotic
neurons ( Rhee et al., 2012 ).
In a genetic screen in zebrafish designed for identification of regulators of
endodermal organ development, two Dnmt1 loss of function mutants were
identified that affect pancreatic development. Loss of DNMT1 resulted in
normal formation of liver and pancreas but these organs begin to degenerate
after 84 h postfertilization. Although DNA replication and entry into mitosis
were unaffected, the acinar cells were almost abolished by 100 h after fertil-
ization. Endocrine cells on the other hand were unaffected and unexpect-
edly downregulation of Dnmt1 by morpholinos resulted in pancreatic