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1.
Hum Mutat ; 42(4): 392-407, 2021 04.
Artigo em Inglês | MEDLINE | ID: mdl-33382518

RESUMO

Idiopathic scoliosis (IS) is a spinal disorder affecting up to 3% of otherwise healthy children. IS has a strong familial genetic component and is believed to be genetically complex due to significant variability in phenotype and heritability. Previous studies identified putative loci and variants possibly contributing to IS susceptibility, including within extracellular matrix, cilia, and actin networks, but the genetic architecture and underlying mechanisms remain unresolved. Here, we used whole-exome sequencing from three affected individuals in a multigenerational family with IS and identified 19 uncommon variants (minor allele frequency < 0.05). Genotyping of additional family members identified a candidate heterozygous variant (H1115Q, G>C, rs142032413) within the ciliary gene KIF7, a regulator within the hedgehog (Hh) signaling pathway. Resequencing of the second cohort of unrelated IS individuals and controls identified several severe mutations in KIF7 in affected individuals only. Subsequently, we generated a mutant zebrafish model of kif7 using CRISPR-Cas9. kif7co63/co63 zebrafish displayed severe scoliosis, presenting in juveniles and progressing through adulthood. We observed no deformities in the brain, Reissner fiber, or central canal cilia in kif7co63/co63 embryos, although alterations were seen in Hh pathway gene expression. This study suggests defects in KIF7-dependent Hh signaling, which may drive pathogenesis in a subset of individuals with IS.


Assuntos
Cinesinas , Escoliose , Peixe-Zebra , Animais , Cílios/metabolismo , Humanos , Cinesinas/genética , Mutação , Escoliose/genética , Peixe-Zebra/genética , Proteínas de Peixe-Zebra
2.
Sci Immunol ; 5(53)2020 11 20.
Artigo em Inglês | MEDLINE | ID: mdl-33219153

RESUMO

Innate lymphoid cells (ILCs) develop from common lymphoid progenitors (CLPs), which further differentiate into the common ILC progenitor (CILP) that can give rise to both ILCs and natural killer (NK) cells. Murine ILC intermediates have recently been characterized, but the human counterparts and their developmental trajectories have not yet been identified, largely due to the lack of homologous surface receptors in both organisms. Here, we show that human CILPs (CD34+CD117+α4ß7+Lin-) acquire CD48 and CD52, which define NK progenitors (NKPs) and ILC precursors (ILCPs). Two distinct NK cell subsets were generated in vitro from CD34+CD117+α4ß7+Lin-CD48-CD52+ and CD34+CD117+α4ß7+Lin-CD48+CD52+ NKPs, respectively. Independent of NKPs, ILCPs exist in the CD34+CD117+α4ß7+Lin-CD48+CD52+ subset and give rise to ILC1s, ILC2s, and NCR+ ILC3s, whereas CD34+CD117+α4ß7+Lin-CD48+CD52- ILCPs give rise to a distinct subset of ILC3s that have lymphoid tissue inducer (LTi)-like properties. In addition, CD48-expressing CD34+CD117+α4ß7+Lin- precursors give rise to tissue-associated ILCs in vivo. We also observed that the interaction of 2B4 with CD48 induced differentiation of ILC2s, and together, these findings show that expression of CD48 by human ILCPs modulates ILC differentiation.


Assuntos
Antígeno CD48/metabolismo , Diferenciação Celular/imunologia , Células Matadoras Naturais/fisiologia , Células Progenitoras Linfoides/fisiologia , Família de Moléculas de Sinalização da Ativação Linfocitária/metabolismo , Animais , Antígeno CD52/metabolismo , Separação Celular , Células Cultivadas , Citometria de Fluxo , Técnicas de Inativação de Genes , Humanos , Imunidade Inata , Camundongos , Cultura Primária de Células , RNA-Seq , Transdução de Sinais/genética , Transdução de Sinais/imunologia , Família de Moléculas de Sinalização da Ativação Linfocitária/genética , Análise de Célula Única , Especificidade da Espécie
3.
Sci Rep ; 10(1): 6335, 2020 04 14.
Artigo em Inglês | MEDLINE | ID: mdl-32286456

RESUMO

Numerous cell types modulate hematopoiesis through soluble and membrane bound molecules. Whether developing hematopoietic progenitors of a particular lineage modulate the differentiation of other hematopoietic lineages is largely unknown. Here we aimed to investigate the influence of myeloid progenitors on CD34+ cell differentiation into CD56+ innate lymphocytes. Sorted CD34+ cells cultured in the presence of stem cell factor (SCF) and FMS-like tyrosine kinase 3 ligand (FLT3L) give rise to numerous cell types, including progenitors that expressed the prolactin receptor (PRLR). These CD34+PRLR+ myeloid-lineage progenitors were derived from granulocyte monocyte precursors (GMPs) and could develop into granulocytes in the presence of granulocyte-macrophage colony-stimulating factor (GM-CSF) in vitro. Moreover, CD34+PRLR+ myeloid progenitors lacked lymphoid developmental potential, but when stimulated with prolactin (PRL) they increased the differentiation of other CD34+ cell populations into the NK lineage in a non-contact dependent manner. Both mRNA and protein analyses show that PRL increased mothers against decapentaplegic homolog 7 (SMAD7) in CD34+PRLR+ myeloid cells, which reduced the production of transforming growth factor beta 1 (TGF-ß1), a cytokine known to inhibit CD56+ cell development. Thus, we uncover an axis whereby CD34+PRLR+ GMPs inhibit CD56+ lineage development through TGF-ß1 production and PRL stimulation leads to SMAD7 activation, repression of TGF-ß1, resulting in CD56+ cell development.


Assuntos
Células-Tronco Hematopoéticas/metabolismo , Linfopoese/genética , Prolactina/genética , Receptores da Prolactina/genética , Proteína Smad7/genética , Fator de Crescimento Transformador beta1/genética , Antígenos CD34/genética , Antígenos CD34/imunologia , Antígeno CD56/genética , Antígeno CD56/imunologia , Diferenciação Celular/genética , Linhagem da Célula/genética , Regulação da Expressão Gênica no Desenvolvimento/genética , Hematopoese/genética , Células-Tronco Hematopoéticas/citologia , Humanos , Células Matadoras Naturais/citologia , Células Matadoras Naturais/metabolismo , Linfócitos/citologia , Linfócitos/imunologia , Células Progenitoras Mieloides/citologia , Células Progenitoras Mieloides/metabolismo , Tirosina Quinase 3 Semelhante a fms/genética
4.
Front Immunol ; 10: 510, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-30949172

RESUMO

Helper Innate lymphoid cells (ILCs) are tissue resident lymphocytes that play a critical role in a number of biological processes. Several transcription factors are required for the differentiation of hematopoietic stem cells (HSCs) into ILCs. Recent studies demonstrate GATA3 as a transcriptional regulator that plays an essential role in ILC development. We aimed to modulate the differentiation of human cord blood-derived CD34+ cells into ILCs by transient and ectopic expression of mRNA encoding transcription factors known to be important for ILC lineage differentiation, including GATA3, TOX, NFIL3, ID2, and RORγt. Using this experimental protocol, only GATA3 significantly modulated HSCs to differentiate into helper ILCs. Transient overexpression of GATA3 drove the emergence of CD34+α4ß7+ early ILC progenitors during the first few days of culture. These ILC progenitors further acquired IL-7Rα and CD117 to give rise to immediate ILC precursors. In support of these findings, analysis of the genes induced by GATA3 in HSCs showed an upregulation of those associated with ILC development. Moreover, we show GATA3 also acts on more committed progenitors and significantly shifts the differentiation of progenitors away from the ILC1/NK lineage to the ILC2 and ILC3 lineage. In summary, transient overexpression of GATA3 mRNA in CD34+ HSCs enhances the differentiation of HSCs into the helper ILC lineages, at the expense of NK cell development.


Assuntos
Diferenciação Celular/imunologia , Fator de Transcrição GATA3/imunologia , Regulação da Expressão Gênica/imunologia , Células-Tronco Hematopoéticas/imunologia , Imunidade Inata , Linfócitos T Auxiliares-Indutores/imunologia , Células-Tronco Hematopoéticas/citologia , Humanos , Linfócitos T Auxiliares-Indutores/citologia
5.
Chem Sci ; 6(7): 4049-4053, 2015 Jul 01.
Artigo em Inglês | MEDLINE | ID: mdl-29218170

RESUMO

Macrocycle-to-framework strategy was explored to prepare covalent organic frameworks (COFs) using shape-persistent macrocycles as multitopic building blocks. We demonstrate well-ordered mesoporous 2D COFs (AEM-COF-1 and AEM-COF-2) can be constructed from tritopic arylene-ethynylene macrocycles, which determine the topology and modulate the porosity of the materials. According to PXRD analysis and computer modelling study, these COFs adopt the fully eclipsed AA stacking mode with large accessible pore sizes of 34 or 39 Å, which are in good agreement with the values calculated by NLDFT modelling of gas adsorption isotherms. The pore size of COFs can be effectively expanded by using larger size of the macrocycles. Provided a plethora of polygonal shape-persistent macrocycles with various size, shape and internal cavity, macrocycle-to-framework strategy opens up a promising approach to expand the structural diversity of COFs and build hierarchical pore structures within the framework.

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