An Lmx1b–miR135a2 regulatory circuit modulates Wnt1/Wnt signaling and determines the size of the midbrain dopaminergic progenitor pool
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MicroRNAs regulate gene expression in diverse physiological scenarios. Their role in the control of morphogen related signaling pathways has been less studied, particularly in the context of embryonic Central Nervous System (CNS) development. Here, we uncover a role for microRNAs in limiting the spatiotemporal range of morphogen expression and function. Wnt1 is a key morphogen in the embryonic midbrain, and directs proliferation, survival, patterning and neurogenesis. We reveal an autoregulatory negative feedback loop between the transcription factor Lmx1b and a newly characterized microRNA, miR135a2, which modulates the extent of Wnt1/Wnt signaling and the size of the dopamine progenitor domain. Conditional gain of function studies reveal that Lmx1b promotes Wnt1/Wnt signaling, and thereby increases midbrain size and dopamine progenitor allocation. Conditional removal of Lmx1b has the opposite effect, in that expansion of the dopamine progenitor domain is severely compromised. Next, we provide evidence that microRNAs are involved in restricting dopamine progenitor allocation. Conditional loss of Dicer1 in embryonic stem cells (ESCs) results in expanded Lmx1a/b+ progenitors. In contrast, forced elevation of miR135a2 during an early window in vivo phenocopies the Lmx1b conditional knockout. When En1::Cre, but not Shh::Cre or Nes::Cre, is used for recombination, the expansion of Lmx1a/b+ progenitors is selectively reduced. Bioinformatics and luciferase assay data suggests that miR135a2 targets Lmx1b and many genes in the Wnt signaling pathway, including Ccnd1, Gsk3b, and Tcf7l2. Consistent with this, we demonstrate that this mutant displays reductions in the size of the Lmx1b/Wnt1 domain and range of canonical Wnt signaling. We posit that microRNA modulation of the Lmx1b/Wnt axis in the early midbrain/isthmus could determine midbrain size and allocation of dopamine progenitors. Since canonical Wnt activity has recently been recognized as a key ingredient for programming ESCs towards a dopaminergic fate in vitro, these studies could impact the rational design of such protocols.
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The boundaries of the dopamine primordium are defined by transcription factor expression: the caudal extent by the Otx2/Gbx2 boundary, the rostral extent by the En1/Dbx1 boundary, and the dorsal extent by the Lmx1a/Nkx6.1 boundary.
“The caudal extent is defined by the Otx2/Gbx2 boundary coincident with the morphological mid-hindbrain boundary [74]. The rostral extent is defined by the En1/Dbx1 gene expression boundary which is located in the diencephalic region [75–78]. The dorsal extent is defined by the Lmx1a/Nkx6.1 gene expression boundary [71,79–81].”
From Classification of midbrain dopamine neurons using single-cell gene expression profiling approaches (2020) · cites this paper as [81]
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- Authors
- Anderegg, A., Lin, H.-P., Chen, J.-A., Caronia-Brown, G., Cherepanova, N., Yun, B., Joksimovic, M., Rock, J., Harfe, B. D., Johnson, R., & Awatramani, R.
- Affiliations
- Northwestern University (US)
- Institute of Molecular Biology, Academia Sinica (TW)
- University of Florida (US)
- The University of Texas MD Anderson Cancer Center (US)
- Corresponding author
- Awatramani, Rajeshwar
- Venue
- PLoS Genetics
- Publisher
- Public Library of Science (PLoS)
- Published
- 2013-12-12
- Volume
- 9
- Issue
- 12
- Pages
- e1003973
- ISSN
- 1553-7390 (ISSN-L)
- 1553-7404
- PMC
- PMC3861205
- OpenAlex
- W2002526679
- Cited by
- 57
- References
- 73
- Citations by year
- 2025: 3 · 2024: 1 · 2023: 5 · 2022: 1 · 2021: 2 · 2020: 5 · 2019: 10 · 2018: 6 · 2017: 4 · 2016: 4 · 2015: 11 · 2014: 5
- FWCI
- 2.98
- Type
- journal article
- Language
- en
- Open access
- gold
- doi.org
- Licence
- Locations
- PLoS Genetics (publishedVersion, cc-by)
- Europe PMC (PubMed Central) (publishedVersion, cc-by)
- PubMed Central (publishedVersion, cc-by)
- PubMed (publishedVersion)
- DOAJ (DOAJ: Directory of Open Access Journals) (submittedVersion, cc-by-sa)
- eScholarship (California Digital Library) (submittedVersion)
- Figshare (submittedVersion, cc-by)
- Funders
- Brain Research Foundation
- Whitehall Foundation
- Northwestern University
- National Institutes of Health (1f31ns065670-01a2)
- National Institute of Neurological Disorders and Stroke (F31 NS065670, R01NS071081, NRSA NIH 1F31 NS065670-01A2, NIH 1RO1NS071081-01)
- Eunice Kennedy Shriver National Institute of Child Health and Human Development (R01HD052785)
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Developmental Biology and Gene Regulation
- Life Sciences › Neuroscience › Developmental Neuroscience › Neurogenesis and neuroplasticity mechanisms
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Cancer Research › MicroRNA in disease regulation
- Keywords
- Lmx1b, negative feedback loop, microRNA regulation, DICER1, Wnt/β-catenin signaling, GSK3B, TCF7L2, CCND1, dopaminergic differentiation, embryonic stem cells
- MeSH terms
- Animals, Cell Differentiation, Dopamine, Embryo, Mammalian, Humans, Mesencephalon, Parkinson Disease, Transcription Factors, Gene Expression Regulation, Developmental, MicroRNAs, Ribonuclease III, Wnt1 Protein, Mice, DEAD-box RNA Helicases, Embryonic Stem Cells, Neurogenesis, Dopaminergic Neurons, Wnt Signaling Pathway, LIM-Homeodomain Proteins
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