Specification of dopaminergic subsets involves interplay of En1 and Pitx3

Veenvliet, Jesse V.; Santos, Maria T. M. Alves dos; Kouwenhoven, Willemieke M.; Oerthel, Lars von; Lim, Jamie; Linden, Annemarie J. A. van der; Koerkamp, Marian J.A. Groot; Holstege, Frank C.P.; Smidt, Marten P.

doi:10.1242/dev.102731

Cited by 22 publications

(70 citation statements)

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“…Of several investigated MbDN markers only Nr4a2 expression is maintained in both areas (Fig. 2) [105]. The absence of most MbDN markers is reminiscent of the phenotype observed when FGF signaling is ablated in the midbrain, suggesting that EN1 might function downstream of FGF signaling in the specification of midbrain identity in MbDNs [96].…”

Section: Signaling Pathwaysmentioning

confidence: 89%

Establishing diversity in the dopaminergic system

Bodea

Blaess

2015

FEBS Letters

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a b s t r a c tMidbrain dopaminergic neurons (MbDNs) modulate cognitive processes, regulate voluntary movement, and encode reward prediction errors and aversive stimuli. While the degeneration of MbDNs underlies the motor defects in Parkinson's disease, imbalances in dopamine levels are associated with neuropsychiatric disorders such as depression, schizophrenia and substance abuse. In recent years, progress has been made in understanding how MbDNs, which constitute a relatively small neuronal population in the brain, can contribute to such diverse functions and dysfunctions. In particular, important insights have been gained regarding the distinct molecular, neurochemical and network properties of MbDNs. How this diversity of MbDNs is established during brain development is only starting to be unraveled. In this review, we summarize the current knowledge on the diversity in MbDN progenitors and differentiated MbDNs in the developing rodent brain. We discuss the signaling pathways, transcription factors and transmembrane receptors that contribute to setting up these diverse MbDN subpopulations. A better insight into the processes that establish diversity in MbDNs will ultimately improve the understanding of the architecture and function of the dopaminergic system in the adult brain.

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Section: Signaling Pathwaysmentioning

confidence: 89%

Establishing diversity in the dopaminergic system

Bodea

Blaess

2015

FEBS Letters

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“…The PBX family of transcription factors is composed of four members in mammals (PBX1-4) (Moens & Selleri, 2006;Longobardi et al, 2013). Expression of Pbx genes has been detected in both the mouse and human midbrain as well as mDAn (Thompson et al, 2006;Yin et al, 2009;Ganat et al, 2012;Sgado et al, 2012;Veenvliet et al, 2013). However, to date only a very mild mDAn axon guidance phenotype has been described in Pbx1 null embryos (Sgado et al, 2012).…”

Section: Introductionmentioning

confidence: 99%

A PBX1 transcriptional network controls dopaminergic neuron development and is impaired in Parkinson's disease

Villaescusa

Toledo

et al. 2016

The EMBO Journal

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Pre-B-cell leukemia homeobox (PBX) transcription factors are known to regulate organogenesis, but their molecular targets and function in midbrain dopaminergic neurons (mDAn) as well as their role in neurodegenerative diseases are unknown. Here, we show that PBX1 controls a novel transcriptional network required for mDAn specification and survival, which is sufficient to generate mDAn from human stem cells. Mechanistically, PBX1 plays a dual role in transcription by directly repressing or activating genes, such as Onecut2 to inhibit lateral fates during embryogenesis, Pitx3 to promote mDAn development, and Nfe2l1 to protect from oxidative stress. Notably, PBX1 and NFE2L1 levels are severely reduced in dopaminergic neurons of the substantia nigra of Parkinson's disease (PD) patients and decreased NFE2L1 levels increases damage by oxidative stress in human midbrain cells. Thus, our results reveal novel roles for PBX1 and its transcriptional network in mDAn development and PD, opening the door for new therapeutic interventions.

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“…It was shown that En1/2 survival activity on mDA neurons in these mice could be mediated through both, the activation of Erk1/2 MAPK survival pathway and suppression of the pro-apoptotic activity of the pro-neurotrophin receptor p75NTR [10]. Finally, a recent study also analyzed En1À/À mice, which are viable on a C57BL/6 background, and reported a much more rapid and pronounced postnatal loss of mDA neurons [35]. All these observations support the idea that En1/2 continues to be required for the survival and/or maintenance of a subset of mDA neurons during adulthood.…”

Section: Progressive Loss Of Mda Neurons In En1+/à Micementioning

confidence: 99%

Dissecting the role of Engrailed in adult dopaminergic neurons – Insights into Parkinson disease pathogenesis

et al. 2015

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Edited by Wilhelm JustKeywords: Dopaminergic neuron Homeoprotein Parkinson disease Engrailed Mitochondria Substantia nigra pars compacta Retrograde degeneration a b s t r a c tThe homeoprotein Engrailed (Engrailed-1/Engrailed-2, collectively En1/2) is not only a survival factor for mesencephalic dopaminergic (mDA) neurons during development, but continues to exert neuroprotective and physiological functions in adult mDA neurons. Loss of one En1 allele in the mouse leads to progressive demise of mDA neurons in the ventral midbrain starting from 6 weeks of age. These mice also develop Parkinson disease-like motor and non-motor symptoms. The characterization of En1 heterozygous mice have revealed striking parallels to central mechanisms of Parkinson disease pathogenesis, mainly related to mitochondrial dysfunction and retrograde degeneration. Thanks to the ability of homeoproteins to transduce cells, En1/2 proteins have also been used to protect mDA neurons in various experimental models of Parkinson disease. This neuroprotection is partly linked to the ability of En1/2 to regulate the translation of certain nuclear-encoded mitochondrial mRNAs for complex I subunits. Other transcription factors that govern mDA neuron development (e.g. Foxa1/2, Lmx1a/b, Nurr1, Otx2, Pitx3) also continue to function for the survival and maintenance of mDA neurons in the adult and act through partially overlapping but also diverse mechanisms.

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Specification of dopaminergic subsets involves interplay of En1 and Pitx3

Cited by 22 publications

References 0 publications

Establishing diversity in the dopaminergic system

Establishing diversity in the dopaminergic system

A PBX1 transcriptional network controls dopaminergic neuron development and is impaired in Parkinson's disease

Dissecting the role of Engrailed in adult dopaminergic neurons – Insights into Parkinson disease pathogenesis

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