Gata2 and Gata3 regulate the differentiation of serotonergic and glutamatergic neuron subtypes of the dorsal raphe

Haugas, Maarja; Tikker, Laura; Achim, Kaia; Salminen, Marjo; Partanen, Juha

doi:10.1242/dev.136614

Cited by 27 publications

(43 citation statements)

References 52 publications

(97 reference statements)

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“…The majority of Pet-1 −/− neurons no longer produce 5-HT, although some maintain enough expression of the 5-HT gene battery to continue synthesis (Kiyasova et al, 2011), likely due to continued expression of Lmx1b. Some subsets of 5-HT neurons primarily in the medial DRN and MRN also express the vesicular glutamate transporter type 3 (vGlut3) enabling the packaging of glutamate into vesicles for release (Rood et al, 2014; Haugas et al, 2016). In Pet-1 −/− neurons, vGlut3 expression is decreased likely resulting in decreased ability to package and release glutamate in that subset neurons.…”

Section: Discussionmentioning

confidence: 99%

“…Other transcription factors that are expressed and/or regulated by Pet-1 in 5-HT neurons likely contribute to 5-HT neuron heterogeneity including Lmx1b, Gata2, Gata3, En1 , and others described above (Ding et al, 2003; Zhao Z.-Q. et al, 2006; Zhao et al, 2007; Song et al, 2011; Yan et al, 2013; Haugas et al, 2016). …”

Section: Control Of Maturation By Pet-1mentioning

confidence: 95%

“…Each of these TFs do not require the others for their initial activation and all three maintain expression throughout life. In a recent study, it has now been shown that Gata2 and Gata3 have an additional role in generating a subtype of 5-HT neurons in the DRN that express the vesicular glutamate transporter ( Slc17a8 , vGlut3) (Haugas et al, 2016). …”

Section: Summary Of the Regulatory Network Controlling 5-ht Neuronmentioning

confidence: 99%

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Regulatory Mechanisms Controlling Maturation of Serotonin Neuron Identity and Function

Spencer

Deneris

2017

Front. Cell. Neurosci.

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The brain serotonin (5-hydroxytryptamine; 5-HT) system has been extensively studied for its role in normal physiology and behavior, as well as, neuropsychiatric disorders. The broad influence of 5-HT on brain function, is in part due to the vast connectivity pattern of 5-HT-producing neurons throughout the CNS. 5-HT neurons are born and terminally specified midway through embryogenesis, then enter a protracted period of maturation, where they functionally integrate into CNS circuitry and then are maintained throughout life. The transcriptional regulatory networks controlling progenitor cell generation and terminal specification of 5-HT neurons are relatively well-understood, yet the factors controlling 5-HT neuron maturation are only recently coming to light. In this review, we first provide an update on the regulatory network controlling 5-HT neuron development, then delve deeper into the properties and regulatory strategies governing 5-HT neuron maturation. In particular, we discuss the role of the 5-HT neuron terminal selector transcription factor (TF) Pet-1 as a key regulator of 5-HT neuron maturation. Pet-1 was originally shown to positively regulate genes needed for 5-HT synthesis, reuptake and vesicular transport, hence 5-HT neuron-type transmitter identity. It has now been shown to regulate, both positively and negatively, many other categories of genes in 5-HT neurons including ion channels, GPCRs, transporters, neuropeptides, and other transcription factors. Its function as a terminal selector results in the maturation of 5-HT neuron excitability, firing characteristics, and synaptic modulation by several neurotransmitters. Furthermore, there is a temporal requirement for Pet-1 in the control of postmitotic gene expression trajectories thus indicating a direct role in 5-HT neuron maturation. Proper regulation of the maturation of cellular identity is critical for normal neuronal functioning and perturbations in the gene regulatory networks controlling these processes may result in long-lasting changes in brain function in adulthood. Further study of 5-HT neuron gene regulatory networks is likely to provide additional insight into how neurons acquire their mature identities and how terminal selector-type TFs function in postmitotic vertebrate neurons.

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Section: Discussionmentioning

confidence: 99%

Section: Control Of Maturation By Pet-1mentioning

confidence: 95%

Section: Summary Of the Regulatory Network Controlling 5-ht Neuronmentioning

confidence: 99%

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Regulatory Mechanisms Controlling Maturation of Serotonin Neuron Identity and Function

Spencer

Deneris

2017

Front. Cell. Neurosci.

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“…For example, GATA2 and GATA3 perform important regulatory functions at different stages of neuronal development. In the hindbrain, GATA2 and GATA3 act redundantly during neuronal specification, but also play unique roles as selectors in subsequent stages of neuronal differentiation toward the serotonergic and glutamatergic lineages (Craven et al, 2004;Haugas et al, 2016;Lahti et al, 2016). A unique role for GATA2 has also been identified for the development of sympathetic (Tsarovina et al, 2004) and GABAergic neurons (Kala et al, 2009;Willett and Greene, 2011).…”

Section: Other Ectoderm-derived Tissuesmentioning

confidence: 99%

GATA transcription factors in development and disease

2018

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The GATA family of transcription factors is of crucial importance during embryonic development, playing complex and widespread roles in cell fate decisions and tissue morphogenesis. GATA proteins are essential for the development of tissues derived from all three germ layers, including the skin, brain, gonads, liver, hematopoietic, cardiovascular and urogenital systems. The crucial activity of GATA factors is underscored by the fact that inactivating mutations in most GATA members lead to embryonic lethality in mouse models and are often associated with developmental diseases in humans. In this Primer, we discuss the unique and redundant functions of GATA proteins in tissue morphogenesis, with an emphasis on their regulation of lineage specification and early organogenesis.

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“…This suggests that some of the observed changes could be connected to decreased striatal DA levels during development. The downregulation of the postmitotic selector Gata3, involved in differentiation of SNc and VTA GABAergic neurons, indicates a potential developmental effect of DAT:TH KO(Haugas et al 2016;Moriguchi 2006).…”

mentioning

confidence: 99%

Transcriptome responses to reduced dopamine in the Substantia Nigra Pars Compacta reveals a potential protective role for dopamine

Koltun

Cichewicz

Gibbs

et al. 2018

Preprint

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Parkinson's Disease (PD), is a neurodegenerative disorder affecting both cognitive and motor functions. It is characterized by decreased brain dopamine (DA) and a selective and progressive loss of dopaminergic neurons in the substantia nigra pars compacta (SNc), whereas dopaminergic neurons in the ventral tegmental area (VTA) show reduced vulnerability. The majority of animal models of PD are genetic lesion or neurotoxin exposure models that lead to death of dopaminergic neurons. Here we use a DAT:TH KO mouse model that by inactivation of the tyrosine hydroxylase (Th) gene in dopamine transporter-expressing neurons, causes selective depletion of striatal dopamine without affecting DA neuron survival. We analyzed transcriptome responses to decreased DA in both pre-and post-synaptic dopaminergic brain regions of DAT:TH KO animals. We detected only few differentially expressed genes in the post-synaptic regions as a function of DA deficiency. This suggests that the broad striatal transcriptional changes in neurodegeneration-based PD models are not direct effects of DA depletion, but are rather a result of DA neuronal death. However, we find a number of dopaminergic genes differentially expressed in SNc, and to a lesser extent in VTA, as a function of DA deficiency, providing evidence for a DA-dependent feedback loop. Of particular interest, expression of Nr4a2, a crucial transcription factor maintaining DA neuron identity, is significantly decreased in SNc, but not VTA, of DAT:TH KO mice, implying a potential protective role for DA in the SNc.

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Gata2 and Gata3 regulate the differentiation of serotonergic and glutamatergic neuron subtypes of the dorsal raphe

Cited by 27 publications

References 52 publications

Regulatory Mechanisms Controlling Maturation of Serotonin Neuron Identity and Function

Regulatory Mechanisms Controlling Maturation of Serotonin Neuron Identity and Function

GATA transcription factors in development and disease

Transcriptome responses to reduced dopamine in the Substantia Nigra Pars Compacta reveals a potential protective role for dopamine

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