NKX2-1 Is Required in the Embryonic Septum for Cholinergic System Development, Learning, and Memory

Magno, Lorenza; Barry, Caswell; Schmidt-Hieber, Christoph; Theodotou, Polyvios; Häusser, Michael; Kessaris, Nicoletta

doi:10.1016/j.celrep.2017.07.053

Cited by 68 publications

(111 citation statements)

References 52 publications

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“…The significant marker on chromosome 21 is adjacent to the genes PAX9 and NKX2-1 (Fig 7c). Previous works suggested that PAX9 is required for the chondrogenic differentiation of sclerotomal cells during embryogenesis [35, 36], and that NKX2 is required for the embryonic development of cholinergic septohippocampal projection neurons [37]. Moreover, according to PathCards, NKX2-1 is part of the embryo pre-implementation path [38].…”

Section: Discussionmentioning

confidence: 99%

Genetic and genomic analysis of early abortions in Israeli dairy cattle

Gershoni

Ezra²,

Weller

2019

Preprint

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20Female infertility accounts for at least 50% of all human infertility cases. One of the causes 21 contributing for female infertility is embryo loss after fertilization. Previous findings suggested 22 that more than half of fertilizations results in embryo loss before pregnancy is detected. Dairy 23 cattle may be a useful model for study of the genetic architecture of this trait. In advanced 24 commercial populations, all breeding is by artificial insemination, and extensive records of the 25 cows' estrus, insemination and pregnancies are available. We proposed re-insemination between 26 49 and 100 days after the first insemination as an indicator trait for early abortion in dairy cattle, 27 based on the mean estrus interval of 21 days. Israeli Holstein cows scored as early abortion were 28 compare to cows recorded as pregnant from the first insemination. This trait was compare to 29 conception rate from first insemination. Animal model variance components were estimated by 30 REML, including parents and grandparents of cows with records. First parity heritability for 31 conception rate was 3%. In the multi-trait analysis of parities 1-3 for abortion rate heritabilities 32 ranged from 8.9% for first parity to 10.4% for second parity. The variance component for the 33 service sire effect for abortion rate were less than half the variance component for conception 34 rate. Thus genetic control of the two traits is clearly different. Genome wide association study 35 were performed based on the genetic evaluations of ~1200 sires with reliabilities >50%. The 36 markers with the lowest probabilities for early abortion were also included among the markers 37 with the lowest probabilities for conception rate, but not vice versa. The marker explaining the 38 most variance for abortion rate is located within the ABCA9 gene, which is found within an 39 ABC genes cluster. The ATP-binding cassette family is the major class of primary active 40 transporters in the placenta. 3 41 42 Author summary 43 44 Approximately 70% of human conceptions fail to achieve viability. Almost 50% of all 45 pregnancies end in miscarriage before the clinical recognition of a missed period. Cattle are a 46 useful model for human female reproductive processes, because of the similarities in the 47 reproductive cycles, and the extensive documentation in commercial cattle populations, 48including estrus and insemination records. In addition to the expected benefits from cow fertility 49 research for human biomedical applications, fertility is an economically important trait in dairy 50 cattle with very low heritability. The mean estrous interval for cattle is 21 days. We therefore 51 proposed re-insemination between 49 and 100 days after the first insemination as an indicator 52 trait for early abortion. Israeli Holstein cows scored as having early abortion based on first 53 insemination after parturition were compare to cows recorded as pregnant from the first 54 insemination. Heritability for early abortion rate was three-fold the herit...

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Section: Discussionmentioning

confidence: 99%

Genetic and genomic analysis of early abortions in Israeli dairy cattle

Gershoni

Ezra²,

Weller

2019

Preprint

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“…The NKX2‐1 gene is expressed in the lung bud and thyroid primordium during embryogenesis and continues to be expressed in adult human lung and thyroid . In thyroid tissue, NKX2‐1 is instrumental in the formation of the thyroid bud and is important in the functional differentiation of the gland in late development and postnatally . In the lung, NKX2‐1 is a key regulator of pulmonary development and homeostasis, active in promotion of branching morphogenesis and epithelial lineage differentiation …”

Section: Discussionmentioning

confidence: 99%

“…17 In thyroid tissue, NKX2-1 is instrumental in the formation of the thyroid bud and is important in the functional differentiation of the gland in late development and postnatally. 27 In the lung, NKX2-1 is a key regulator of pulmonary development and homeostasis, active in promotion of branching morphogenesis and epithelial lineage differentiation. 28 A review of the genetics of NKX2-1 describes 77 known pathogenic variants.…”

Section: Discussionmentioning

confidence: 99%

Is Benign Hereditary Chorea Really Benign? Brain‐Lung‐Thyroid Syndrome Caused by NKX2‐1 Mutations

Parnes

Bashir

Jankovic

2018

Movement Disord Clin Pract

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Background Since its localization to the NKX2‐1 gene in 2002, the phenotype of the disorder historically called “benign hereditary chorea” has been expanding beyond chorea. Methods The phenomenology of movement disorders and other symptomatology associated with mutations in NKX2‐1 were characterized after a detailed evaluation of consecutive patients evaluated in our clinic over the past 3 years. Results We studied 5 patients (3 females), ages 2 to 31 years, with confirmed pathogenic variants in NKX2‐1. All patients exhibited chorea, gross motor delay, and gait impairment. Other symptoms included neonatal respiratory failure (n = 4), cognitive deficits (n = 3), hypothyroidism (n = 4), joint laxity (n = 2), myoclonus (n = 1), hypotonia (n = 3), and seizures (n = 1). Chorea often proved refractory to medical therapies. Conclusions The phenotype associated with pathogenic variants in NKX2‐1 frequently includes disabling and often medically refractory neurological and non‐neurological abnormalities. We therefore suggest that the term benign hereditary chorea be abandoned in favor of its genetic designation as NKX2‐1–related disorder.

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“…The functional implications of molecular heterogeneity in striatal CINs are at present not well understood (Munoz-Manchado et al, 2018) (Lozovaya et al, 2018) (Magno et al, 2017). CINs originate from distinct areas of the subpallium which give rise to heterogeneous populations of cholinergic cells in the forebrain (Ahmed et al, 2019).…”

Section: Control Of the Cholinergic Cell Identitymentioning

confidence: 99%

“…Recent findings suggest that developmental differentiation factors induce some degree of functional diversity amongst CINs, thus enabling them to acquire unique properties (Magno et al, 2017) (Lozovaya et al, 2018) (Ahmed et al, 2019). However, the functional relevance of this heterogeneity remains unclear.…”

Section: Introductionmentioning

confidence: 99%

Loss of the Er81 Transcription Factor in Cholinergic Cells Alters Striatal Activity and Habit Formation

Ranjbar-Slamloo

Ahmed

Abed

et al. 2020

Preprint

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Highlights-The Er81 transcription factor is expressed in striatal cholinergic interneurons (CINs) -Conditional deletion of Er81 alters key molecular, morphological and electrophysiological properties of CINs in adult mice -Deletion of Er81 reduces the intrinsic excitability of CINs by upregulating delayed rectifier and hyperpolarization-activated currents -Deletion of Er81 alters in vivo striatal activity and habit formation SUMMARYThe finely-tuned activity of cholinergic interneurons (CINs) in the striatum is key for motor control, learning, and habit formation. Yet, the molecular mechanisms that determine their unique functional properties remain poorly explored. Using a combination of genetic and biochemical assays, in vitro and in vivo physiological characterisation, we report that selective ablation of the Er81 transcription factor leads to prominent changes in CIN molecular, morphological and electrophysiological features. In particular, the lack of Er81 amplifies intrinsic delayed-rectifier and hyperpolarization-activated currents, which subsequently alters the tonic and phasic activity of CINs. We further demonstrate that these alterations enhance their pause and time-locked responses to sensorimotor inputs in awake mice. Finally, this study reveals an Er81-dependent developmental mechanism in CINs essential for habit formation in adult mice. RESULTS Er81 is expressed in the striatal cholinergic interneuronsWe first analysed the expression of Er81 from birth to adulthood and found that both mRNA ( Figure 1A) and protein levels (Figure 1B) significantly drop from postnatal day 6 (P6) to P30 in the total striatum. In the CINs specifically, we observed similar decrease of Er81 protein levels from P6 to P30 (Figure 1C). To determine the proportion of CINs expressing Er81 at any stage during development, we analysed β-galactosidase staining, which perdures long after being synthesised (Dehorter et al., 2015). We found that most of CINs (62 ± 7 %) in the Er81 nlsLacZ/+ mice express β-galactosidase (and therefore Er81) in the striatum (Figure S1A), unlike cholinergic cells in the basal forebrain (6 ± 2%; Figure S1B). As Er81 can have an important role in cell function (Dehorter et al., 2015), we analysed the consequences of removing Er81 from CINs, using conditional knockout mice (cKO: ChAT-Cre; Er81 f/f ; comparing with control mice: ChAT-Cre; Er81 +/+ ). We did not observe any change in cholinergic cell density at P2 and P30 within the striatum between control and Er81 cKO conditions (Figure 1D-Fsuggesting that the specific deletion of Er81 does not affect CIN neurogenesis and migration. Cholinergic interneuron properties change in the absence of Er81To determine the role of Er81 in CIN specification and maturation, we assessed the molecular properties of these cells following Er81 deletion. The LIM homeodomain transcription factorLhx6 is expressed in about half of striatal CINs (Lozovaya et al., 2018)and is necessary for MGE-derived GABAergic interneuron specification (Liodis et al., 2007) (Fragkouli et al., ...

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NKX2-1 Is Required in the Embryonic Septum for Cholinergic System Development, Learning, and Memory

Cited by 68 publications

References 52 publications

Genetic and genomic analysis of early abortions in Israeli dairy cattle

Genetic and genomic analysis of early abortions in Israeli dairy cattle

Is Benign Hereditary Chorea Really Benign? Brain‐Lung‐Thyroid Syndrome Caused by NKX2‐1 Mutations

Loss of the Er81 Transcription Factor in Cholinergic Cells Alters Striatal Activity and Habit Formation

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