Forebrain Ptf1a Is Required for Sexual Differentiation of the Brain

Fujiyama, Tomoyuki; Miyashita, Satoshi; Tsuneoka, Yousuke; Kanemaru, Kazumasa; Kakizaki, Miyo; Kanno, Sanae; Ishikawa, Yukiko; Yamashita, Mariko; Owa, Tomoo; Nagaoka, Mai; Kawaguchi, Yoshiya; Yanagawa, Yuchio; Magnuson, Mark A.; Muratani, Masafumi; Shibuya, Akira; Nabeshima, Yo Ichi; Yanagisawa, Masashi; Funato, Hiromasa; Hoshino, Mikio

doi:10.1016/j.celrep.2018.06.010

Cited by 25 publications

(27 citation statements)

References 49 publications

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“…The PTF1A-PRDM13 axis in Kiss1 neuron development. Previous studies showed that PRDM13 functions downstream of PTF1A, which plays distinct roles in the regulation of both the cerebellum and the hypothalamus (20,21,40). Our observations support the existence of overlapping phenotypes between Prdm13-and Ptf1a-deficient mice in the hypothalamus and cerebellum, implying that a transcriptional dysregulation in specific neuronal progenitors is the most likely pathogenic mechanism underlying the phenotypes associated with PRDM13 mutation.…”

Section: Discussionsupporting

confidence: 86%

“…Recessive mutations of PTF1A are associated with pancreatic and cerebellar agenesis/hypoplasia (39). Further, PTF1A was recently found to be required for the development of the hypothalamus in the mouse, where its forebrain-specific deletion leads to disruption of the Kiss1 neuronal system, hypogonadism and altered sexual behaviours, via a mechanism that does not involve a GABAergic/glutamatergic imbalance (40). These findings suggest the possibility that PTF1A or PRDM13 mutations may be responsible for some congenital disorders characterized by both cerebellar hypoplasia and CHH.…”

Section: Introductionmentioning

confidence: 93%

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A recessive PRDM13 mutation results in congenital hypogonadotropic hypogonadism and cerebellar hypoplasia

Whittaker

Oleari

Gregory

et al. 2021

Preprint

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PRDM13 (PR Domain containing 13) is a putative chromatin modifier and transcriptional regulator that functions downstream of the transcription factor PTF1A, which in turn controls GABAergic fate in the spinal cord and neuronal development in the hypothalamus. Here, we report a novel, recessive syndrome associated with PRDM13 mutation. Patients exhibited intellectual disability, ataxia with cerebellar hypoplasia, scoliosis and delayed puberty with congenital hypogonadotropic hypogonadism (CHH). Expression studies revealed Prdm13/PRDM13 transcripts in the developing hypothalamus and cerebellum in mouse and human. We investigated the development of hypothalamic neurons and the cerebellum in mice homozygous for a Prdm13 mutant allele. A significant reduction in the number of Kisspeptin (Kiss1) neurons in the hypothalamus and PAX2+ progenitors emerging from the cerebellar ventricular zone were observed. The latter was accompanied by ectopic expression of the glutamatergic lineage marker TLX3. Phenotypically, mice lacking PRDM13 displayed cerebellar hypoplasia, normal gonadal structure, but delayed pubertal onset. Together, these findings identify PRDM13 as a critical regulator of GABAergic cell fate in the cerebellum and of kisspeptin neuron development in the hypothalamus, providing a mechanistic explanation for the co-occurrence of CHH and cerebellar hypoplasia in this syndrome. To our knowledge, this is the first evidence linking disrupted PRDM13-mediated regulation of Kiss1 neurons to CHH in humans.

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Section: Discussionsupporting

confidence: 86%

Section: Introductionmentioning

confidence: 93%

A recessive PRDM13 mutation results in congenital hypogonadotropic hypogonadism and cerebellar hypoplasia

Whittaker

Oleari

Gregory

et al. 2021

Preprint

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“…Given the parallels between DA neurons/ coronet cells and the hypothalamus, it seems reasonable to suggest that the regulatory "cocktail" of Ptf1a and Meis might also control the development of DA neuronal cell types in vertebrates. Indeed, Ptf1a has been suggested to play a role in the specification of DA neurons in the hypothalamus in mice (Fujiyama et al 2018), while Meis TFs have been implicated in the specification of DA neurons in the olfactory bulb (Agoston et al 2014) and hypothalamus (Hook et al 2018) in mice.…”

Section: Resultsmentioning

confidence: 99%

Regulatory cocktail for dopaminergic neurons in a protovertebrate identified by whole-embryo single-cell transcriptomics

Horie

Chen

et al. 2018

Genes Dev.

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The CNS of the protovertebrate contains a single cluster of dopaminergic (DA) neurons, the coronet cells, which have been likened to the hypothalamus of vertebrates. Whole-embryo single-cell RNA sequencing (RNA-seq) assays identified as the most strongly expressed cell-specific transcription factor (TF) in DA/coronet cells. Knockdown of activity results in their loss, while misexpression results in the appearance of supernumerary DA/coronet cells. Photoreceptor cells and ependymal cells are the most susceptible to transformation, and both cell types express high levels of Coexpression of both and caused the wholesale transformation of the entire CNS into DA/coronet cells. We therefore suggest that the reiterative use of functional manipulations and single-cell RNA-seq assays is an effective means for the identification of regulatory cocktails underlying the specification of specific cell identities.

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“…Elastase-CreERTM , Rosa26R , Rosa26-RFP and Ptf1a floxed mice were previously described 27 – 30 . By mating, we obtained Elastase-CreERTM; Ptf1a floxed / floxed ; Rosa26R or Rosa26-RFP mice (Ptf1a cKO mice) in which Ptf1a -deleted cells are detected as X-gal(+) or RFP(+) cells after tamoxifen injection.…”

Section: Methodsmentioning

confidence: 99%

Ptf1a inactivation in adult pancreatic acinar cells causes apoptosis through activation of the endoplasmic reticulum stress pathway

Sakikubo

Furuyama

Horiguchi

et al. 2018

Sci Rep

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Pancreas transcription factor 1 subunit alpha (PTF1A) is one of the key regulators in pancreatogenesis. In adults, it transcribes digestive enzymes, but its other functions remain largely unknown. Recent conditional knockout studies using Ptf1aCreER/floxed heterozygous mouse models have found PTF1A contributes to the identity maintenance of acinar cells and prevents tumorigenesis caused by the oncogenic gene Kras. However, Ptf1a heterozygote is known to behave differently from homozygote. To elucidate the effects of Ptf1a homozygous loss, we prepared Elastase-CreERTM; Ptf1afloxed/floxed mice and found that homozygous Ptf1a deletion in adult acinar cells causes severe apoptosis. Electron microscopy revealed endoplasmic reticulum (ER) stress, a known cause of unfolded protein responses (UPR). We confirmed that UPR was upregulated by the activating transcription factor 6 (ATF6) and protein kinase RNA (PKR)-like endoplasmic reticulum kinase (PERK) pathways, but not the inositol requiring enzyme 1 (IRE1) pathway. Furthermore, we detected the expression of CCAAT-enhancer-binding protein (C/EBP) homologous protein (CHOP), a pro-apoptotic factor, indicating the apoptosis was induced through UPR. Our homozygous model helps clarify the role PTF1A has on the homeostasis and pathogenesis of exocrine pancreas in mice.

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Forebrain Ptf1a Is Required for Sexual Differentiation of the Brain

Cited by 25 publications

References 49 publications

A recessive PRDM13 mutation results in congenital hypogonadotropic hypogonadism and cerebellar hypoplasia

A recessive PRDM13 mutation results in congenital hypogonadotropic hypogonadism and cerebellar hypoplasia

Regulatory cocktail for dopaminergic neurons in a protovertebrate identified by whole-embryo single-cell transcriptomics

Ptf1a inactivation in adult pancreatic acinar cells causes apoptosis through activation of the endoplasmic reticulum stress pathway

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