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Query: UMLS:C0030567 (
Parkinson's disease
)
63,064
document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)
The embryonic formation of midbrain dopaminergic (mDA) neurons
in vivo
provides critical guidelines for the
in vitro
differentiation of mDA neurons from stem cells, which are currently being developed for
Parkinson's disease
cell replacement therapy. Bone morphogenetic protein (BMP)/SMAD inhibition is routinely used during early steps of stem cell differentiation protocols, including for the generation of mDA neurons. However, the function of the BMP/SMAD pathway for
in vivo
specification of mammalian mDA neurons is virtually unknown. Here, we report that BMP5/7-deficient mice (
Bmp5
-/-
;
Bmp7
-/-
) lack mDA neurons due to reduced neurogenesis in the mDA progenitor domain. As molecular mechanisms accounting for these alterations in
Bmp5
-/-
;
Bmp7
-/-
mutants, we have identified expression changes of the BMP/SMAD target genes MSX1/2 (
msh homeobox 1
/2) and SHH (sonic hedgehog). Conditionally inactivating SMAD1 in neural stem cells of mice
in vivo
(
Smad1
Nes
) hampered the differentiation of progenitor cells into mDA neurons by preventing cell cycle exit, especially of TH
+
SOX6
+
(tyrosine hydroxylase, SRY-box 6) and TH
+
GIRK2
+
(potassium voltage-gated channel subfamily-J member-6) substantia nigra neurons. BMP5/7 robustly increased the
in vitro
differentiation of human induced pluripotent stem cells and induced neural stem cells to mDA neurons by up to threefold. In conclusion, we have identified BMP/SMAD signaling as a novel critical pathway orchestrating essential steps of mammalian mDA neurogenesis
in vivo
that balances progenitor proliferation and differentiation. Moreover, we demonstrate the potential of BMPs to improve the generation of stem-cell-derived mDA neurons
in vitro
, highlighting the importance of sequential BMP/SMAD inhibition and activation in this process.
SIGNIFICANCE STATEMENT
We identify bone morphogenetic protein (BMP)/SMAD signaling as a novel essential pathway regulating the development of mammalian midbrain dopaminergic (mDA) neurons
in vivo
and provide insights into the molecular mechanisms of this process. BMP5/7 regulate MSX1/2 (
msh homeobox 1
/2) and SHH (sonic hedgehog) expression to direct mDA neurogenesis. Moreover, the BMP signaling component SMAD1 controls the differentiation of mDA progenitors, particularly to substantia nigra neurons, by directing their cell cycle exit. Importantly, BMP5/7 increase robustly the differentiation of human induced pluripotent and induced neural stem cells to mDA neurons. BMP/SMAD are routinely inhibited in initial stages of stem cell differentiation protocols currently being developed for
Parkinson's disease
cell replacement therapies. Therefore, our findings on opposing roles of the BMP/SMAD pathway during
in vitro
mDA neurogenesis might improve these procedures significantly.
...
PMID:BMP/SMAD Pathway Promotes Neurogenesis of Midbrain Dopaminergic Neurons
In Vivo
and in Human Induced Pluripotent and Neural Stem Cells. 2999 64
