Mammalian-Specific Sequences in Pou3f2 Contribute to Maternal Behavior

Nasu, Makoto; Yada, Saori; Igarashi, Atsushi; Sutoo, Den'etsu; Akiyama, Kayo; Ito, Meguru; Yoshida, Nobuaki; Ueda, Shintaroh

doi:10.1093/gbe/evu072

Cited by 21 publications

(20 citation statements)

References 45 publications

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“…Previous studies have indicated that male mice have a weaker ability to identify novel objects compared with female mice (Frick & Gresack 2003;Ghi et al 1999;Sutcliffe et al 2007), consistent with our observation. Our present observation is also consistent with our previous finding of impaired pup recognition in Pou3f2 Δ/Δ dams (Nasu et al 2014). In the object location test, Pou3f2 Δ/Δ mice also exhibited impairments in spatial cognition.…”

Section: Discussionsupporting

confidence: 93%

“…Our present observation is also consistent with our previous finding of impaired pup recognition in Pou3f2 Δ/Δ dams (Nasu et al . ). In the object location test, Pou3f2 Δ/Δ mice also exhibited impairments in spatial cognition.…”

Section: Discussionmentioning

confidence: 97%

“…In our previous study, Pou3f2 Δ/Δ mice showed decreased brain levels of tryptophan hydroxylase and tyrosine hydroxylase (Nasu et al . ). Accumulating evidence shows that serotonin and dopamine are closely related to mammalian cognitive function (Jay et al .…”

Section: Discussionmentioning

confidence: 97%

“…We previously reported that homopolymeric amino acid repeats in POU3F2 affect murine behavior (Nasu et al 2014). We generated two types of knock-in mice: Pou3f2 tro/tro mice, in which the entire coding region of Pou3f2 is replaced with the amphibian (Xenopus tropicalis) ortholog (lacking homopolymeric repeats), and Pou3f2 Δ/Δ mice, in which all three homopolymeric amino acid repeats are deleted from the transactivation domain.…”

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confidence: 99%

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POU3F2 participates in cognitive function and adult hippocampal neurogenesis via mammalian‐characteristic amino acid repeats

Hashizume

Yamanaka

Ueda

2017

Genes Brain and Behavior

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POU3F2/BRN-2 is a transcription factor that is mainly expressed in the central nervous system and plays an important role in brain development. The transactivation domain of POU3F2 includes multiple mammalian-characteristic tandem amino acid repeats (homopolymeric amino acid repeats). We previously generated knock-in mice (Pou3f2 mice) in which all three homopolymeric amino acid repeats were deleted from the Pou3f2 transactivation domain and identified phenotypic impairments in maternal behavior and pup recognition. Yet, the exact biological implications of homopolymeric repeats are not completely understood. In this study, we investigated cognitive function and hippocampal neurogenesis in Pou3f2 mice. Pou3f2 mice exhibited cognitive impairment in object recognition and object location tests. Immunohistochemistry for doublecortin, a marker of immature neurons, showed a lower number of newborn neurons in the dentate gyrus of adult Pou3f2 mice compared with wild-type mice. Consistent with this observation, adult Pou3f2 mice had lower numbers of 5-bromo-2'-deoxyuridine (BrdU) and NeuN double-positive cells at 4 weeks after BrdU injection compared with control mice, indicating the decreased generation of mature granule cells in Pou3f2 mice. Taken together, these results suggest that POU3F2 is involved in cognitive function as well as adult hippocampal neurogenesis, and that homopolymeric amino acid repeats in this gene play a functional role.

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Section: Discussionsupporting

confidence: 93%

Section: Discussionmentioning

confidence: 97%

Section: Discussionmentioning

confidence: 97%

mentioning

confidence: 99%

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POU3F2 participates in cognitive function and adult hippocampal neurogenesis via mammalian‐characteristic amino acid repeats

Hashizume

Yamanaka

Ueda

2017

Genes Brain and Behavior

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“…For example, deletion of the polyglutamine tract in mouse huntingtin results in subtle behavioural changes relating to learning and memory and motor coordination [63]. Replacement of mouse POU3F2 with a Xenopus orthologue that lacks polyglutamine tracts and other homopolymer amino acid repeats resulted in neurochemical changes and a dramatic deterioration in pup retrieval behaviour [64]. The polyglutamine tract in mouse SRY has important roles in protein stabilization and transcriptional activation that are essential for sex determination [65].…”

Section: Discussionmentioning

confidence: 99%

Functional characterization of rare FOXP2 variants in neurodevelopmental disorder

Estruch

Graham

Chinnappa

et al. 2016

J Neurodevelop Disord

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BackgroundHeterozygous disruption of FOXP2 causes a rare form of speech and language impairment. Screens of the FOXP2 sequence in individuals with speech/language-related disorders have identified several rare protein-altering variants, but their phenotypic relevance is often unclear. FOXP2 encodes a transcription factor with a forkhead box DNA-binding domain, but little is known about the functions of protein regions outside this domain.MethodsWe performed detailed functional analyses of seven rare FOXP2 variants found in affected cases, including three which have not been previously characterized, testing intracellular localization, transcriptional regulation, dimerization, and interaction with other proteins. To shed further light on molecular functions of FOXP2, we characterized the interaction between this transcription factor and co-repressor proteins of the C-terminal binding protein (CTBP) family. Finally, we analysed the functional significance of the polyglutamine tracts in FOXP2, since tract length variations have been reported in cases of neurodevelopmental disorder.ResultsWe confirmed etiological roles of multiple FOXP2 variants. Of three variants that have been suggested to cause speech/language disorder, but never before been characterized, only one showed functional effects. For the other two, we found no effects on protein function in any assays, suggesting that they are incidental to the phenotype. We identified a CTBP-binding region within the N-terminal portion of FOXP2. This region includes two amino acid substitutions that occurred on the human lineage following the split from chimpanzees. However, we did not observe any effects of these amino acid changes on CTBP binding or other core aspects of FOXP2 function. Finally, we found that FOXP2 variants with reduced polyglutamine tracts did not exhibit altered behaviour in cellular assays, indicating that such tracts are non-essential for core aspects of FOXP2 function, and that tract variation is unlikely to be a highly penetrant cause of speech/language disorder.ConclusionsOur findings highlight the importance of functional characterization of novel rare variants in FOXP2 in assessing the contribution of such variants to speech/language disorder and provide further insights into the molecular function of the FOXP2 protein.Electronic supplementary materialThe online version of this article (doi:10.1186/s11689-016-9177-2) contains supplementary material, which is available to authorized users.

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Serotonin neuron development: shaping molecular and structural identities

Deneris

Gaspar

2017

WIREs Developmental Biology

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The continuing fascination with serotonin (5-hydroxytryptamine, 5-HT) as a nervous system chemical messenger began with its discovery in the brains of mammals in 1953. Among the many reasons for this decades-long interest is that the small numbers of neurons that make 5-HT influence the excitability of neural circuits in nearly every region of the brain and spinal cord. A further reason is that 5-HT dysfunction has been linked to a range of psychiatric and neurological disorders many of which have a neurodevelopmental component. This has led to intense interest in understanding 5-HT neuron development with the aim of determining whether early alterations in their generation lead to brain disease susceptibility. Here, we present an overview of the neuroanatomical organization of vertebrate 5-HT neurons, their neurogenesis, and prodigious axonal architectures, which enables the expansive reach of 5-HT neuromodulation in the central nervous system. We review recent findings that have revealed the molecular basis for the tremendous diversity of 5-HT neuron subtypes, the impact of environmental factors on 5-HT neuron development, and how 5-HT axons are topographically organized through disparate signaling pathways. We summarize studies of the gene regulatory networks that control the differentiation, maturation, and maintenance of 5-HT neurons. These studies show that the regulatory factors controlling acquisition of 5-HT-type transmitter identity continue to play critical roles in the functional maturation and the maintenance of 5-HT neurons. New insights are presented into how continuously expressed 5-HT regulatory factors control 5-HT neurons at different stages of life and how the regulatory networks themselves are maintained. © 2017 Wiley Periodicals, Inc. How to cite this article:WIREs Dev Biol 2018, 7:e301. doi: 10.1002/wdev.301 INTRODUCTIONI n all species harboring a nervous system, from invertebrates to mammals, a small percentage of brainstem neurons become specialized to use serotonin (5-hydroxytryptamine, 5-HT) as a neurotransmitter. [1][2][3][4] Unlike glutamate or Gaba, the main excitatory and inhibitory neurotransmitters of the brain, the action of 5-HT is that of a neuromodulator, adjusting neuronal excitability, to increase or decrease cell excitability according to the 5-HT receptors engaged. 5,6 Moreover, 5-HT has long-term effects on cell function such as trophic effects on growth. 7,8 Although the pool of 5-HT that is made in the brain accounts for a small percentage of total body 5-HT synthesis, brain 5-HT has been implicated in a multitude of functions from basic homeostatic processes such as thermoregulation and breathing, 9,10 to more elaborate functions such as affect and mood control, [11][12][13][14][15][16] memory, 17 and reward. 18 5-HT also of 26plays a key role in several complex social behaviors such as male dominance, aggressive behavior, and maternal care. [19][20][21][22][23][24][25][26][27] In mammals, all brain 5-HT neurons are generated in a part of the developing hindbrain cal...

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Mammalian-Specific Sequences in Pou3f2 Contribute to Maternal Behavior

Cited by 21 publications

References 45 publications

POU3F2 participates in cognitive function and adult hippocampal neurogenesis via mammalian‐characteristic amino acid repeats

POU3F2 participates in cognitive function and adult hippocampal neurogenesis via mammalian‐characteristic amino acid repeats

Functional characterization of rare FOXP2 variants in neurodevelopmental disorder

Serotonin neuron development: shaping molecular and structural identities

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