scholarly journals The BMP antagonist Gremlin1 contributes to the development of cortical excitatory neurons, motor balance and fear responses

Development ◽  
2021 ◽  
Author(s):  
Mari Ichinose ◽  
Nobumi Suzuki ◽  
Tongtong Wang ◽  
Hiroki Kobayashi ◽  
Laura Vrbanac ◽  
...  
Keyword(s):  
Lineage Tracing ◽  
Bmp Signaling ◽  
Conditional Knockout ◽  
Embryonic Mouse ◽  
Glutamatergic Neurons ◽  
Functional Maturation ◽  
Morphogenetic Protein ◽  
Dorsal Telencephalon ◽  
Endogenous Modulators ◽  
Bmp Antagonist

Bone morphogenetic protein (BMP) signaling is required for early forebrain development and cortical formation. How the endogenous modulators of BMP signaling regulate the structural and functional maturation of the developing brain remains unclear. Here we show that expression of the BMP antagonist, Grem1, marks committed layer Ⅴ and Ⅵ glutamatergic neurons in the embryonic mouse brain. Lineage tracing of Grem1-expressing cells in the embryonic brain was examined by administration of tamoxifen to pregnant Grem1creERT; Rosa26LSLTdtomato mice at 13.5 days post coitum (dpc), followed by collection of embryos later in gestation. In addition, at 14.5 dpc, bulk mRNA seq analysis of differentially expressed transcripts between FACS sorted Grem1 positive and negative cells was performed. We also generated Emx1-cre mediated Grem1 conditional knockout mice (Emx1-Cre;Grem1flox/flox) in which the Grem1 gene was deleted specifically in the dorsal telencephalon. Grem1Emx1cKO animals had reduced cortical thickness, especially layers Ⅴ and Ⅵ and impaired motor balance and fear sensitivity compared to littermate controls. This study has revealed new roles for Grem1 in the structural and functional maturation of the developing cortex.

scholarly journals The BMP antagonist Gremlin1 contributes to the development of cortical excitatory neurons, motor balance and fear responses

2020 ◽  
Author(s):  
Mari Ichinose ◽  
Nobumi Suzuki ◽  
Tongtong Wang ◽  
Hiroki Kobayashi ◽  
Laura Vrbanac ◽  
...  
Keyword(s):  
Mouse Brain ◽  
Knockout Mice ◽  
Lineage Tracing ◽  
Bmp Signaling ◽  
Conditional Knockout ◽  
Embryonic Mouse ◽  
Glutamatergic Neurons ◽  
Conditional Knockout Mice ◽  
Functional Maturation ◽  
Bmp Antagonist

AbstractBone morphogenetic protein (BMP) signaling is required for early forebrain development and cortical formation. How the endogenous modulators of BMP signaling regulate the structural and functional maturation of the developing brain remains unclear. Here we show that expression of the BMP antagonist, Grem1, marks a neuroprogenitor that gives rise to layer V and VI glutamatergic neurons in the embryonic mouse brain. Lineage tracing of Grem1-expressing cells in the embryonic brain was examined by administration of tamoxifen to pregnant Grem1creERT Rosa26LSLTdtomato mice at 13.5 days post coitum (dpc), followed by collection of embryos later in gestation. In addition, at 14.5 dpc, bulk mRNA seq analysis of differentially expressed transcripts between FACS sorted Grem1 positive and negative cells was performed. We also generated Emx1-cre mediated Grem1 conditional knockout mice (Emx1-Cre;Grem1flox/flox) in which the Grem1 gene was deleted specifically in the dorsal telencephalon. Grem1Emx1cKO animals had reduced cortical thickness, especially layers V and VI and impaired motor balance and fear sensitivity compared to littermate controls. This study has revealed new roles for Grem1 in the structural and functional maturation of the developing cortex.Summary statementThe BMP antagonist, Grem1, marks neuroprogenitors that give rise to deep layer glutamatergic neurons in the embryonic mouse brain. Grem1 conditional knockout mice display cortical and behavioural abnormalities.

scholarly journals Follistatin is critical for mouse uterine receptivity and decidualization

2017 ◽  
Vol 114 (24) ◽  
pp. E4772-E4781 ◽  
Author(s):  
Paul T. Fullerton ◽  
Diana Monsivais ◽  
Ramakrishna Kommagani ◽  
Martin M. Matzuk
Keyword(s):  
Molecular Mechanisms ◽  
Recurrent Miscarriage ◽  
Embryo Implantation ◽  
Bmp Signaling ◽  
Conditional Knockout ◽  
Uterine Receptivity ◽  
Vitro Fertilization ◽  
Morphogenetic Protein ◽  
Proliferation And Differentiation

Embryo implantation remains a significant challenge for assisted reproductive technology, with implantation failure occurring in ∼50% of in vitro fertilization attempts. Understanding the molecular mechanisms underlying uterine receptivity will enable the development of new interventions and biomarkers. TGFβ family signaling in the uterus is critical for establishing and maintaining pregnancy. Follistatin (FST) regulates TGFβ family signaling by selectively binding TGFβ family ligands and sequestering them. In humans, FST is up-regulated in the decidua during early pregnancy, and women with recurrent miscarriage have lower endometrial expression of FST during the luteal phase. Because global knockout of Fst is perinatal lethal in mice, we generated a conditional knockout (cKO) of Fst in the uterus using progesterone receptor-cre to study the roles of uterine Fst during pregnancy. Uterine Fst-cKO mice demonstrate severe fertility defects and deliver only 2% of the number of pups delivered by control females. In Fst-cKO mice, the uterine luminal epithelium does not respond properly to estrogen and progesterone signals and remains unreceptive to embryo attachment by continuing to proliferate and failing to differentiate. The uterine stroma of Fst-cKO mice also responds poorly to artificial decidualization, with lower levels of proliferation and differentiation. In the absence of uterine FST, activin B expression and signaling are up-regulated, and bone morphogenetic protein (BMP) signals are impaired. Our findings support a model in which repression of activin signaling by FST enables uterine receptivity by preserving critical BMP signaling.

scholarly journals Hormone-Responsive BMP Signaling Expands Myoepithelial Cell Lineages and Prevents Alveolar Precocity in Mammary Gland

2021 ◽  
Vol 9 ◽  
Author(s):  
Chunlei Shao ◽  
Pengbo Lou ◽  
Ruiqi Liu ◽  
Xueyun Bi ◽  
Guilin Li ◽  
...  
Keyword(s):  
Mammary Gland ◽  
Myoepithelial Cells ◽  
Bmp Signaling ◽  
Conditional Knockout ◽  
Signaling Mechanism ◽  
Knockout Mouse Model ◽  
Conditional Knockout Mouse ◽  
Morphogenetic Protein ◽  
Organ Systems ◽  
Mammary Stem

Myoepithelial and luminal cells synergistically expand in the mammary gland during pregnancy, and this process is precisely governed by hormone-related signaling pathways. The bone morphogenetic protein (BMP) signaling pathway is now known to play crucial roles in all organ systems. However, the functions of BMP signaling in the mammary gland remain unclear. Here, we found that BMPR1a is upregulated by hormone-induced Sp1 at pregnancy. Using a doxycycline (Dox)-inducible BMPR1a conditional knockout mouse model, we demonstrated that loss of BMPR1a in myoepithelium results in compromised myoepithelial integrity, reduced mammary stem cells and precocious alveolar differentiation during pregnancy. Mechanistically, BMPR1a regulates the expression of p63 and Slug, two key regulators of myoepithelial maintenance, through pSmad1/5-Smad4 complexes, and consequently activate P-cadherin during pregnancy. Furthermore, we observed that loss of BMPR1a in myoepithelium results in the upregulation of a secreted protein Spp1 that could account for the precocious alveolar differentiation in luminal layer, suggesting a defective basal-to-luminal paracrine signaling mechanism. Collectively, these findings identify a novel role of BMP signaling in maintaining the identity of myoepithelial cells and suppressing precocious alveolar formation.

Bone Morphogenetic Protein 2 Coordinates Early Tooth Mineralization

2018 ◽  
Vol 97 (7) ◽  
pp. 835-843 ◽  
Author(s):  
Z. Malik ◽  
M. Alexiou ◽  
B. Hallgrimsson ◽  
A.N. Economides ◽  
H.U. Luder ◽  
...  
Keyword(s):  
Tooth Development ◽  
Bmp Signaling ◽  
Conditional Knockout ◽  
Bone Morphogenetic Protein 2 ◽  
Micro Computed Tomography ◽  
Tooth Mineralization ◽  
Morphogenetic Protein ◽  
Dental Hard Tissues ◽  
Dentin Sialoprotein ◽  
Tooth Germs

Formation of highly organized dental hard tissues is a complex process involving sequential and ordered deposition of an extracellular scaffold, followed by its mineralization. Odontoblast and ameloblast differentiation involves reciprocal and sequential epithelial-mesenchymal interactions. Similar to early tooth development, various Bmps are expressed during this process, although their functions have not been explored in detail. Here, we investigated the role of odontoblast-derived Bmp2 for tooth mineralization using Bmp2 conditional knockout mice. In developing molars, Bmp2LacZ reporter mice revealed restricted expression of Bmp2 in early polarized and functional odontoblasts while it was not expressed in mature odontoblasts. Loss of Bmp2 in neural crest cells, which includes all dental mesenchyme, caused a delay in dentin and enamel deposition. Immunohistochemistry for nestin and dentin sialoprotein (Dsp) revealed polarization defects in odontoblasts, indicative of a role for Bmp2 in odontoblast organization. Surprisingly, pSmad1/5/8, an indicator of Bmp signaling, was predominantly reduced in ameloblasts, with reduced expression of amelogenin ( Amlx), ameloblastin ( Ambn), and matrix metalloproteinase ( Mmp20). Quantitative real-time polymerase chain reaction (RT-qPCR) analysis and immunohistochemistry showed that loss of Bmp2 resulted in increased expression of the Wnt antagonists dickkopf 1 ( Dkk1) in the epithelium and sclerostin ( Sost) in mesenchyme and epithelium. Odontoblasts showed reduced Wnt signaling, which is important for odontoblast differentiation, and a strong reduction in dentin sialophosphoprotein ( Dspp) but not collagen 1 a1 ( Col1a1) expression. Mature Bmp2-deficient teeth, which were obtained by transplanting tooth germs from Bmp2-deficient embryos under a kidney capsule, showed a dentinogenesis imperfecta type II–like appearance. Micro–computed tomography and scanning electron microscopy revealed reduced dentin and enamel thickness, indistinguishable primary and secondary dentin, and deposition of ectopic osteodentin. This establishes that Bmp2 provides an early temporal, nonredundant signal for directed and organized tooth mineralization.

BMPR-IA signaling is required for the formation of the apical ectodermal ridge and dorsal-ventral patterning of the limb

Development ◽  
2001 ◽  
Vol 128 (22) ◽  
pp. 4449-4461 ◽  
Author(s):  
Kyung Ahn ◽  
Yuji Mishina ◽  
Mark C. Hanks ◽  
Richard R. Behringer ◽  
E. Bryan Crenshaw
Keyword(s):  
Limb Development ◽  
Apical Ectodermal Ridge ◽  
Bmp Signaling ◽  
Conditional Knockout ◽  
Limb Bud ◽  
Gene Encoding ◽  
Bone Morphogenetic Protein Receptor ◽  
Protein Receptor ◽  
Morphogenetic Protein ◽  
Embryonic Limb

We demonstrate that signaling via the bone morphogenetic protein receptor IA (BMPR-IA) is required to establish two of the three cardinal axes of the limb: the proximal-distal axis and the dorsal-ventral axis. We generated a conditional knockout of the gene encoding BMPR-IA (Bmpr) that disrupted BMP signaling in the limb ectoderm. In the most severely affected embryos, this conditional mutation resulted in gross malformations of the limbs with complete agenesis of the hindlimbs. The proximal-distal axis is specified by the apical ectodermal ridge (AER), which forms from limb ectoderm at the distal tip of the embryonic limb bud. Analyses of the expression of molecular markers, such as Fgf8, demonstrate that formation of the AER was disrupted in the Bmpr mutants. Along the dorsal/ventral axis, loss of engrailed 1 (En1) expression in the non-ridge ectoderm of the mutants resulted in a dorsal transformation of the ventral limb structures. The expression pattern of Bmp4 and Bmp7 suggest that these growth factors play an instructive role in specifying dorsoventral pattern in the limb. This study demonstrates that BMPR-IA signaling plays a crucial role in AER formation and in the establishment of the dorsal/ventral patterning during limb development.

scholarly journals Systems biology derived source-sink mechanism of BMP gradient formation

eLife ◽  
2017 ◽  
Vol 6 ◽  
Author(s):  
Joseph Zinski ◽  
Ye Bu ◽  
Xu Wang ◽  
Wei Dou ◽  
David Umulis ◽  
...  
Keyword(s):  
Mathematical Model ◽  
Systems Biology ◽  
Bmp Signaling ◽  
Morphogen Gradient ◽  
Wild Type ◽  
Morphogenetic Protein ◽  
Gradient Formation ◽  
Source Sink ◽  
Bmp Antagonist ◽  
Prevailing View

A morphogen gradient of Bone Morphogenetic Protein (BMP) signaling patterns the dorsoventral embryonic axis of vertebrates and invertebrates. The prevailing view in vertebrates for BMP gradient formation is through a counter-gradient of BMP antagonists, often along with ligand shuttling to generate peak signaling levels. To delineate the mechanism in zebrafish, we precisely quantified the BMP activity gradient in wild-type and mutant embryos and combined these data with a mathematical model-based computational screen to test hypotheses for gradient formation. Our analysis ruled out a BMP shuttling mechanism and a bmp transcriptionally-informed gradient mechanism. Surprisingly, rather than supporting a counter-gradient mechanism, our analyses support a fourth model, a source-sink mechanism, which relies on a restricted BMP antagonist distribution acting as a sink that drives BMP flux dorsally and gradient formation. We measured Bmp2 diffusion and found that it supports the source-sink model, suggesting a new mechanism to shape BMP gradients during development.

scholarly journals The BMP signaling pathway is required together with the FGF pathway for notochord induction in the ascidian embryo

Development ◽  
2001 ◽  
Vol 128 (14) ◽  
pp. 2629-2638 ◽  
Author(s):  
Sébastien Darras ◽  
Hiroki Nishida
Keyword(s):  
Time Window ◽  
Bmp Signaling ◽  
Cell Stage ◽  
Morphogenetic Protein ◽  
Positive Target ◽  
Bmp Pathway ◽  
Notochord Cells ◽  
Bmp Antagonist ◽  
Ascidian Embryo

The 40 notochord cells of the ascidian tadpole invariably arise from two different lineages: the primary (A-line) and the secondary (B-line) lineages. It has been shown that the primary notochord cells are induced by presumptive endoderm blastomeres between the 24-cell and the 64-cell stage. Signaling through the fibroblast growth factor (FGF) pathway is required for this induction. We have investigated the role of the bone morphogenetic protein (BMP) pathway in ascidian notochord formation. HrBMPb (the ascidian BMP2/4 homologue) is expressed in the anterior endoderm at the 44-cell stage before the completion of notochord induction. The BMP antagonist Hrchordin is expressed in a complementary manner in all surrounding blastomeres and appears to be a positive target of the BMP pathway. Unexpectedly, chordin overexpression reduced formation of both primary and secondary notochord. Conversely, primary notochord precursors isolated prior to induction formed notochord in presence of BMP-4 protein. While bFGF protein had a similar activity, notochord precursors showed a different time window of competence to respond to BMP-4 and bFGF. Our data are consistent with bFGF acting from the 24-cell stage, while BMP-4 acts during the 44-cell stage. However, active FGF signaling was also required for induction by BMP-4. In the secondary lineage, notochord specification also required two inducing signals: an FGF signal from anterior and posterior endoderm from the 24-cell stage and a BMP signal from anterior endoderm during the 44-cell stage.

BMP controls proximodistal outgrowth, via induction of the apical ectodermal ridge, and dorsoventral patterning in the vertebrate limb

Development ◽  
2001 ◽  
Vol 128 (22) ◽  
pp. 4463-4474 ◽  
Author(s):  
Sandrine Pizette ◽  
Cory Abate-Shen ◽  
Lee Niswander
Keyword(s):  
Apical Ectodermal Ridge ◽  
Bmp Signaling ◽  
Signal Loss ◽  
Dorsoventral Patterning ◽  
Morphogenetic Protein ◽  
Vertebrate Limb ◽  
Common Signal ◽  
Necessary And Sufficient ◽  
Bmp Antagonist ◽  
Dorsal Pattern

Dorsoventral (DV) patterning of the vertebrate limb requires the function of the transcription factor Engrailed 1 (EN1) in the ventral ectoderm. EN1 restricts, to the dorsal half of the limb, the expression of the two genes known to specify dorsal pattern. Limb growth along the proximodistal (PD) axis is controlled by the apical ectodermal ridge (AER), a specialized epithelium that forms at the distal junction between dorsal and ventral ectoderm. Using retroviral-mediated misexpression of the bone morphogenetic protein (BMP) antagonist Noggin or an activated form of the BMP receptor in the chick limb, we demonstrate that BMP plays a key role in both DV patterning and AER induction. Thus, the DV and PD axes are linked by a common signal. Loss and gain of BMP function experiments show that BMP signaling is both necessary and sufficient to regulate EN1 expression, and consequently DV patterning. Our results also indicate that BMPs are required during induction of the AER. Manipulation of BMP signaling results in either disruptions in the endogenous AER, leading to absent or severely truncated limbs or the formation of ectopic AERs that can direct outgrowth. Moreover, BMP controls the expression of the MSX transcription factors, and our results suggest that MSX acts downstream of BMP in AER induction. We propose that the BMP signal bifurcates at the level of EN1 and MSX to mediate differentially DV patterning and AER induction, respectively.

scholarly journals Anti–USAG-1 therapy for tooth regeneration through enhanced BMP signaling

2021 ◽  
Vol 7 (7) ◽  
pp. eabf1798
Author(s):  
A. Murashima-Suginami ◽  
H. Kiso ◽  
Y. Tokita ◽  
E. Mihara ◽  
Y. Nambu ◽  
...  
Keyword(s):  
Tooth Development ◽  
Bmp Signaling ◽  
Tooth Agenesis ◽  
Tooth Regeneration ◽  
Missing Teeth ◽  
Morphogenetic Protein ◽  
Genetic Abnormalities ◽  
Direct Binding ◽  
Tooth Germs ◽  
Lipoprotein Receptor Related Protein

Uterine sensitization–associated gene-1 (USAG-1) deficiency leads to enhanced bone morphogenetic protein (BMP) signaling, leading to supernumerary teeth formation. Furthermore, antibodies interfering with binding of USAG-1 to BMP, but not lipoprotein receptor–related protein 5/6 (LRP5/6), accelerate tooth development. Since USAG-1 inhibits Wnt and BMP signals, the essential factors for tooth development, via direct binding to BMP and Wnt coreceptor LRP5/6, we hypothesized that USAG-1 plays key regulatory roles in suppressing tooth development. However, the involvement of USAG-1 in various types of congenital tooth agenesis remains unknown. Here, we show that blocking USAG-1 function through USAG-1 knockout or anti–USAG-1 antibody administration relieves congenital tooth agenesis caused by various genetic abnormalities in mice. Our results demonstrate that USAG-1 controls the number of teeth by inhibiting development of potential tooth germs in wild-type or mutant mice missing teeth. Anti–USAG-1 antibody administration is, therefore, a promising approach for tooth regeneration therapy.

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