shh signaling
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2022 ◽  
Vol 17 (1) ◽  
Author(s):  
Ellen C. Gingrich ◽  
Kendra Case ◽  
A. Denise R. Garcia

Abstract Background The molecular signaling pathway, Sonic hedgehog (Shh), is critical for the proper development of the central nervous system. The requirement for Shh signaling in neuronal and oligodendrocyte development in the developing embryo are well established. However, Shh activity is found in discrete subpopulations of astrocytes in the postnatal and adult brain. Whether Shh signaling plays a role in astrocyte development is not well understood. Methods Here, we use a genetic inducible fate mapping approach to mark and follow a population of glial progenitor cells expressing the Shh target gene, Gli1, in the neonatal and postnatal brain. Results In the neonatal brain, Gli1-expressing cells are found in the dorsolateral corner of the subventricular zone (SVZ), a germinal zone harboring astrocyte progenitor cells. Our data show that these cells give rise to half of the cortical astrocyte population, demonstrating their substantial contribution to the cellular composition of the cortex. Further, these data suggest that the cortex harbors astrocytes from different lineages. Gli1 lineage astrocytes are distributed across all cortical layers, positioning them for broad influence over cortical circuits. Finally, we show that Shh activity recurs in mature astrocytes in a lineage-independent manner, suggesting cell-type dependent roles of the pathway in driving astrocyte development and function. Conclusion These data identify a novel role for Shh signaling in cortical astrocyte development and support a growing body of evidence pointing to astrocyte heterogeneity.


2022 ◽  
pp. 002203452110620
Author(s):  
Y. Wu ◽  
H. Kurosaka ◽  
Q. Wang ◽  
T. Inubushi ◽  
K. Nakatsugawa ◽  
...  

Embryonic craniofacial development depends on the coordinated outgrowth and fusion of multiple facial primordia, which are populated with cranial neural crest cells and covered by the facial ectoderm. Any disturbance in these developmental events, their progenitor tissues, or signaling pathways can result in craniofacial deformities such as orofacial clefts, which are among the most common birth defects in humans. In the present study, we show that Rdh10 loss of function leads to a substantial reduction in retinoic acid (RA) signaling in the developing frontonasal process during early embryogenesis, which results in a variety of craniofacial anomalies, including midfacial cleft and ectopic chondrogenic nodules. Elevated apoptosis and perturbed cell proliferation in postmigratory cranial neural crest cells and a substantial reduction in Alx1 and Alx3 transcription in the developing frontonasal process were associated with midfacial cleft in Rdh10-deficient mice. More important, expanded Shh signaling in the ventral forebrain, as well as partial abrogation of midfacial defects in Rdh10 mutants via inhibition of Hh signaling, indicates that misregulation of Shh signaling underlies the pathogenesis of reduced RA signaling-associated midfacial defects. Taken together, these data illustrate the precise spatiotemporal function of Rdh10 and RA signaling during early embryogenesis and their importance in orchestrating molecular and cellular events essential for normal midfacial development.


Biomedicines ◽  
2021 ◽  
Vol 10 (1) ◽  
pp. 32
Author(s):  
James Hentig ◽  
Leah J. Campbell ◽  
Kaylee Cloghessy ◽  
Mijoon Lee ◽  
William Boggess ◽  
...  

Approximately 2 million individuals experience a traumatic brain injury (TBI) every year in the United States. Secondary injury begins within minutes after TBI, with alterations in cellular function and chemical signaling that contribute to excitotoxicity. Post-traumatic seizures (PTS) are experienced in an increasing number of TBI individuals that also display resistance to traditional anti-seizure medications (ASMs). Sonic hedgehog (Shh) is a signaling pathway that is upregulated following central nervous system damage in zebrafish and aids injury-induced regeneration. Using a modified Marmarou weight drop on adult zebrafish, we examined PTS following TBI and Shh modulation. We found that inhibiting Shh signaling by cyclopamine significantly increased PTS in TBI fish, prolonged the timeframe PTS was observed, and decreased survival across all TBI severities. Shh-inhibited TBI fish failed to respond to traditional ASMs, but were attenuated when treated with CNQX, which blocks ionotropic glutamate receptors. We found that the Smoothened agonist, purmorphamine, increased Eaat2a expression in undamaged brains compared to untreated controls, and purmorphamine treatment reduced glutamate excitotoxicity following TBI. Similarly, purmorphamine reduced PTS, edema, and cognitive deficits in TBI fish, while these pathologies were increased and/or prolonged in cyclopamine-treated TBI fish. However, the increased severity of TBI phenotypes with cyclopamine was reduced by cotreating fish with ceftriaxone, which induces Eaat2a expression. Collectively, these data suggest that Shh signaling induces Eaat2a expression and plays a role in regulating TBI-induced glutamate excitotoxicity and TBI sequelae.


2021 ◽  
Vol 9 ◽  
Author(s):  
Haibao Zhang ◽  
Shan Xu ◽  
Dalin He ◽  
Xinyang Wang ◽  
Guodong Zhu

Objectives: Sonic hedgehog (SHH) signaling is important in bladder development. Mice with defective hedgehog signaling develop bladder anomalies. Clinically, urinary tract malformations are reported in human fetuses and infants with mutations of SHH and related signaling pathway genes. Information on the expression of SHH and associated signaling genes in normal human bladder development is fragmentary. This study determined the temporal and spatial expression patterns of SHH signaling pathway components in human fetal bladders by immunohistochemistry (IHC).Material and Methods: Twenty-four bladder specimens from 16 male and 8 female human fetuses aged 12- to 36-week (wk) were obtained from the First Affiliated Hospital of Xi'an Jiaotong University. The tissue slides were processed for IHC staining with SHH, Patched1 (PTC-1), Patched2 (PTC-2), Smoothened (SMO), GLI1 and proliferating cell nuclear antigen (PCNA). The expression levels of each gene were analyzed by semi-quantitative histological scoring system.Results: High intensity of SHH and SMO expression was detected in developing bladder urothelial cells, with no staining in lamina propria (LP), but with minimal expression of SMO in differentiating smooth muscle (SM) layers. The spatial distribution pattern of PTC1 and GLI1 was more complex with minimal expression in the LP layer, moderate expression in the SM layer, and high expression in the urothelium. PTC2 expression was mainly localized in the urothelium and LP, but no expression in the SM layer. All of the SHH signaling components were detected in fetal bladder tissues throughout the development, with expression peaks at 12- and 23-wk, coinciding with high cell proliferation as indicated by PCNA staining in the cell nuclei of urothelium and SM.Conclusions: The autocrine SHH signaling in the developing urothelium, and paracrine SHH signaling in the developing smooth muscle layer, mediated by SMO, PTC-1 and GLI1 were demonstrated during human bladder development. Expression of SHH signaling components peaked at 12-and 23-wk. The first expression peak at 12-wk may relate to urothelium growth, SM induction, and dilation of the bladder cavity. The second expression peaked at 23-wk may relate to urothelium and SM layer differentiation.


2021 ◽  
Author(s):  
Zuzana Vavrusova ◽  
Daniel B Chu ◽  
An Nguyen ◽  
Jennifer L Fish ◽  
Richard A. Schneider

Developmental control of jaw size is crucial to prevent disease and facilitate evolution. We have shown that species-specific differences in jaw size are established by neural crest mesenchyme (NCM), which are the jaw progenitors that migrate into the mandibular primordia. NCM relies on multiple signaling molecules including Sonic Hedgehog (SHH) to mediate interactions with mandibular epithelium that facilitate outgrowth of the jaws. SHH signaling is known to promote outgrowth and so we tested if differential regulation of the SHH pathway can account for species-specific variation in mandibular primordia size. We analyze gene expression of SHH pathway members in duck, chick, and quail, and find higher transcriptional activation in the larger mandibular primordia of duck relative to those of chick and quail. We generate quail-duck chimeras and demonstrate that such activation is NCM-mediated. Gain- and loss-of-function experiments reveal a species-specific response to SHH signaling, with the target Gas1 being most sensitive to manipulations. Gas1 overexpression and knockdown in NCM alters cell number and/or mandibular primordia size. Our work suggests that NCM-mediated changes in SHH signaling may modulate jaw size during development, disease, and evolution.


Author(s):  
Pi En Chang ◽  
Shujin Li ◽  
Hyun-Yi Kim ◽  
Dong-Joon Lee ◽  
Yoon Jeong Choi ◽  
...  

Objectives: Mechanical stimuli are essential for the maintenance of periodontal ligament (PDL) homeostasis. Although there are several studies on atrophic changes in PDL due to occlusal hypofunction, the underlying mechanism is still unknown. Here, we aimed to explore the changes of gene expression in occlusal hypofunctional PDL and elucidate the related role in maintaining the PDL homeostasis.Methods: To investigate the transcriptomic difference between control and hypofunctional PDL tissue from patients, RNA sequencing was performed on 34 human teeth. The atrophic changes in PDL were evaluated by histological analysis. The effect of the Bardet-Biedl syndrome 7 (BBS7) knockdown was evaluated by the RT-qPCR, Western blot, wound healing, and tubule formation assay.Results: We detected that the expression of BBS7 was downregulated in occlusal hypofunctional PDL through RNA sequencing. Dynamic changes, including the number of periodontal ligament cells, alignment of collagen fibers, diameter of blood vessels, appearance of primary cilia, and torturous oxytalan fibers, were observed following occlusal hypofunction. Furthermore, Sonic hedgehog signaling (Shh) activity was closely associated with BBS7 expression in PDL cells. In addition, the cell migration and angiogenesis were also suppressed by BBS7 knockdown in vitro.Conclusion: We suggest that BBS7 plays an essential role in maintaining Shh signaling activity for PDL homeostasis.


Development ◽  
2021 ◽  
Author(s):  
Julie Gamart ◽  
Iros Barozzi ◽  
Frédéric Laurent ◽  
Robert Reinhardt ◽  
Laurène Ramos Martins ◽  
...  

SMAD4 regulates gene expression in response to BMP and TGFβ signal transduction and is required for diverse morphogenetic processes, but its target genes have remained largely elusive. Here, we identify the SMAD4 target genes in mouse limb buds using an epitope-tagged Smad4 allele for ChIP-seq analysis in combination with transcription profiling. This analysis shows that SMAD4 predominantly mediates BMP signal-transduction during early limb bud development. Unexpectedly, the expression of cholesterol biosynthesis enzymes is precociously down-regulated and intracellular cholesterol levels are reduced in Smad4-deficient limb bud mesenchymal progenitors. Most importantly, our analysis reveals a predominant function of SMAD4 in up-regulating target genes in the anterior limb bud mesenchyme. Analysis of differentially expressed genes shared between Smad4- and Shh-deficient limb buds corroborates this function of SMAD4 and also reveals the repressive effect of SMAD4 on posterior genes that are up-regulated in response to SHH signaling. This analysis uncovers opposing trans-regulatory inputs from SHH and SMAD4-mediated BMP signal transduction on anterior and posterior gene expression during the digit patterning and outgrowth in early limb buds.


2021 ◽  
Vol 12 ◽  
Author(s):  
Sung-Eun Kim ◽  
Karla Robles-Lopez ◽  
Xuanye Cao ◽  
Kristyn Liu ◽  
Pooja J. Chothani ◽  
...  

Sonic hedgehog (Shh) signaling regulates multiple morphogenetic processes during embryonic neurogenesis and craniofacial skeletal development. Gpr161 is a known negative regulator of Shh signaling. Nullizygous Gpr161 mice are embryonic lethal, presenting with structural defects involving the neural tube and the craniofacies. However, the lineage specific role of Gpr161 in later embryonic development has not been thoroughly investigated. We studied the Wnt1-Cre lineage specific role of Gpr161 during mouse embryonic development. We observed three major gross morphological phenotypes in Gpr161 cKO (Gpr161 f/f; Wnt1-Cre) fetuses; protrusive tectum defect, encephalocele, and craniofacial skeletal defect. The overall midbrain tissues were expanded and cell proliferation in ventricular zones of midbrain was increased in Gpr161 cKO fetuses, suggesting that protrusive tectal defects in Gpr161 cKO are secondary to the increased proliferation of midbrain neural progenitor cells. Shh signaling activity as well as upstream Wnt signaling activity were increased in midbrain tissues of Gpr161 cKO fetuses. RNA sequencing further suggested that genes in the Shh, Wnt, Fgf and Notch signaling pathways were differentially regulated in the midbrain of Gpr161 cKO fetuses. Finally, we determined that cranial neural crest derived craniofacial bone formation was significantly inhibited in Gpr161 cKO fetuses, which partly explains the development of encephalocele. Our results suggest that Gpr161 plays a distinct role in midbrain development and in the formation of the craniofacial skeleton during mouse embryogenesis.


2021 ◽  
Vol 23 (Supplement_6) ◽  
pp. vi179-vi179
Author(s):  
Foteini Tsiami ◽  
Federica Piccioni ◽  
David Root ◽  
Pratiti Bandopadhayay ◽  
Rosalind Segal ◽  
...  

Abstract Medulloblastoma (MB) is among the most common malignant pediatric brain tumors. Among its four molecularly heterogeneous clinical variants, sonic hedgehog (SHH) subgroup comprises 30% of all MBs and is characterized by constitutive activation of the canonical SHH signaling pathway. Although Smoothened (Smo) inhibition has emerged as a promising therapeutic target for this tumor entity, primary or acquired resistance impedes its clinical efficacy. Thus, further insight into the molecular mechanisms underlying acquired resistance to Smo inhibition are urgently needed to overcome this challenge. Here, we performed a genome-wide CRISPR/Cas9 knockout screen in a murine and a human SHH-MB cell line, SMB21 and DAOY, respectively, in order to unravel tumor-specific genetic vulnerabilities. Our data provide functional evidence that SMB21 cells highly depend on key members of the SHH pathway such as Smo and Gli1 for their survival. In contrast, none of those positive regulators of SHH signaling scored in DAOY cells, suggesting that they are not a faithful human model of this tumor subtype. Of note, functional genomics identified SMB21-context specific essentialities beyond the SHH pathway that include epigenetic regulators such as Dnmt1, Smarca5 and Smarca4. Further in vitro pharmacological validations demonstrate that Dnmt1 inhibition is efficacious in clinically relevant concentrations in SHH-associated cell lines, both sensitive and resistant to Smo inhibition, suggesting novel therapeutic avenues for SHH-MB. By employing genome-scale knockout screens in murine cell lines faithfully recapitulating the biology of human SHH-MB, we aim to decipher synthetic lethal interactors for Dnmt1 inhibitors that could potentially serve as a combinatorial treatment approach for SHH-MB. Finally, genetic ablation and pharmacological inhibition of epigenetic regulators will be evaluated in in vivo mouse models of SHH-MB. Summarizing, our data highlight the potential of inhibitors of epigenetic regulators in SHH-MB sensitive, as well as resistant to Smo inhibition.


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