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  1. Article ; Online: Characterizing post-branching nephrogenesis in the neonatal rabbit

    Meredith P. Schuh / Sunitha Yarlagadda / Lyan Alkhudairy / Kristina Preusse / Raphael Kopan

    Scientific Reports, Vol 13, Iss 1, Pp 1-

    2023  Volume 11

    Abstract: Abstract Human nephrogenesis ends prior to birth in term infants (34–36 week gestation), with most (60%) nephrons forming in late gestation in two post-branching nephrogenesis (PBN) periods: arcading and lateral branch nephrogenesis. Preterm infants, ... ...

    Abstract Abstract Human nephrogenesis ends prior to birth in term infants (34–36 week gestation), with most (60%) nephrons forming in late gestation in two post-branching nephrogenesis (PBN) periods: arcading and lateral branch nephrogenesis. Preterm infants, however, must execute PBN postnatally. Extreme prematurity is associated with low nephron counts. Identifying additional model(s) that undergo PBN postnatally will help support postnatal PBN in preterm infants. The rabbit exhibits longer postnatal nephrogenesis than the mouse but whether it forms nephrons through PBN has not been determined. We performed morphologic and immunohistological assessments of rabbit nephrogenesis from birth (post-conceptual day 31 or 32) to PC49 using H&E and antibodies against SIX1, SIX2, WT1, ZO-1, and JAG1 in the postnatal period. We performed 3D rendering of the nephrogenic niche to assess for PBN, and supplemented the staining with RNAScope to map the expression of Six1, Six2 (nephron progenitors, NPC), and Ret (ureteric bud tip) transcripts to determine the nephrogenic niche postnatal lifespan. Unlike the mouse, rabbit SIX2 disappeared from NPC before SIX1, resembling the human niche. Active nephrogenesis as defined by the presence of SIX1 + naïve NPC/tip population persisted only until PC35–36 (3–5 postnatal days). 3D morphologic assessments of the cortical nephrons identified an elongated tubule with attached glomeruli extending below the UB tip, consistent with PBN arcades, but not with lateral branch nephrogenesis. We conclude that the rabbit shows morphologic and molecular evidence of PBN arcades continuing postnatally for a shorter period than previously thought. The rabbit is the first non-primate expressing SIX1 in the progenitor population. Our findings suggest that studies of arcading in postnatal nephrogenic niche should be performed within the first 5 days of life in the rabbit.
    Keywords Medicine ; R ; Science ; Q
    Subject code 630
    Language English
    Publishing date 2023-11-01T00:00:00Z
    Publisher Nature Portfolio
    Document type Article ; Online
    Database BASE - Bielefeld Academic Search Engine (life sciences selection)

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  2. Article ; Online: Notch dimerization and gene dosage are important for normal heart development, intestinal stem cell maintenance, and splenic marginal zone B-cell homeostasis during mite infestation.

    Francis M Kobia / Kristina Preusse / Quanhui Dai / Nicholas Weaver / Matthew R Hass / Praneet Chaturvedi / Sarah J Stein / Warren S Pear / Zhenyu Yuan / Rhett A Kovall / Yi Kuang / Natanel Eafergen / David Sprinzak / Brian Gebelein / Eric W Brunskill / Raphael Kopan

    PLoS Biology, Vol 18, Iss 10, p e

    2020  Volume 3000850

    Abstract: Cooperative DNA binding is a key feature of transcriptional regulation. Here we examined the role of cooperativity in Notch signaling by CRISPR-mediated engineering of mice in which neither Notch1 nor Notch2 can homo- or heterodimerize, essential for ... ...

    Abstract Cooperative DNA binding is a key feature of transcriptional regulation. Here we examined the role of cooperativity in Notch signaling by CRISPR-mediated engineering of mice in which neither Notch1 nor Notch2 can homo- or heterodimerize, essential for cooperative binding to sequence-paired sites (SPS) located near many Notch-regulated genes. Although most known Notch-dependent phenotypes were unaffected in Notch1/2 dimer-deficient mice, a subset of tissues proved highly sensitive to loss of cooperativity. These phenotypes include heart development, compromised viability in combination with low gene dose, and the gut, developing ulcerative colitis in response to 1% dextran sulfate sodium (DSS). The most striking phenotypes-gender imbalance and splenic marginal zone B-cell lymphoma-emerged in combination with gene dose reduction or when challenged by chronic fur mite infestation. This study highlights the role of the environment in malignancy and colitis and is consistent with Notch-dependent anti-parasite immune responses being compromised in Notch dimer-deficient animals.
    Keywords Biology (General) ; QH301-705.5
    Subject code 570
    Language English
    Publishing date 2020-10-01T00:00:00Z
    Publisher Public Library of Science (PLoS)
    Document type Article ; Online
    Database BASE - Bielefeld Academic Search Engine (life sciences selection)

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  3. Article ; Online: Enhancer architecture sensitizes cell specific responses to Notch gene dose via a bind and discard mechanism

    Yi Kuang / Ohad Golan / Kristina Preusse / Brittany Cain / Collin J Christensen / Joseph Salomone / Ian Campbell / FearGod V Okwubido-Williams / Matthew R Hass / Zhenyu Yuan / Nathanel Eafergan / Kenneth H Moberg / Rhett A Kovall / Raphael Kopan / David Sprinzak / Brian Gebelein

    eLife, Vol

    2020  Volume 9

    Abstract: Notch pathway haploinsufficiency can cause severe developmental syndromes with highly variable penetrance. Currently, we have a limited mechanistic understanding of phenotype variability due to gene dosage. Here, we unexpectedly found that inserting an ... ...

    Abstract Notch pathway haploinsufficiency can cause severe developmental syndromes with highly variable penetrance. Currently, we have a limited mechanistic understanding of phenotype variability due to gene dosage. Here, we unexpectedly found that inserting an enhancer containing pioneer transcription factor sites coupled to Notch dimer sites can induce a subset of Notch haploinsufficiency phenotypes in Drosophila with wild type Notch gene dose. Using Drosophila genetics, we show that this enhancer induces Notch phenotypes in a Cdk8-dependent, transcription-independent manner. We further combined mathematical modeling with quantitative trait and expression analysis to build a model that describes how changes in Notch signal production versus degradation differentially impact cellular outcomes that require long versus short signal duration. Altogether, these findings support a ‘bind and discard’ mechanism in which enhancers with specific binding sites promote rapid Cdk8-dependent Notch turnover, and thereby reduce Notch-dependent transcription at other loci and sensitize tissues to gene dose based upon signal duration.
    Keywords Notch signaling ; Cdk8-Kinase module ; enhancer ; transcription factor binding sites ; degradation ; haploinsufficiency ; Medicine ; R ; Science ; Q ; Biology (General) ; QH301-705.5
    Subject code 570
    Language English
    Publishing date 2020-04-01T00:00:00Z
    Publisher eLife Sciences Publications Ltd
    Document type Article ; Online
    Database BASE - Bielefeld Academic Search Engine (life sciences selection)

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