Transcription Factor MEIS1 Research Articles

Molecular basis of facilitated target search and sequence discrimination of TALE homeodomain transcription factor Meis1

Transcription factors specifically bind to their consensus sequence motifs and regulate transcription efficiency. Transcription factors are also able to non-specifically contact the phosphate backbone of DNA through electrostatic interaction. The homeodomain of Meis1 TALE human transcription factor (Meis1-HD) recognizes its target DNA sequences via two DNA contact regions, the L1-α1 region and the α3 helix (specific binding mode). This study demonstrates that the non-specific binding mode of Meis1-HD is the energetically favored process during DNA binding, achieved by the interaction of the L1-α1 region with the phosphate backbone. An NMR dynamics study suggests that non-specific binding might set up an intermediate structure which can then rapidly and easily find the consensus region on a long section of genomic DNA in a facilitated binding process. Structural analysis using NMR and molecular dynamics shows that key structural distortions in the Meis1-HD–DNA complex are induced by various single nucleotide mutations in the consensus sequence, resulting in decreased DNA binding affinity. Collectively, our results elucidate the detailed molecular mechanism of how Meis1-HD recognizes single nucleotide mutations within its consensus sequence: (i) through the conformational features of the α3 helix; and (ii) by the dynamic features (rigid or flexible) of the L1 loop and the α3 helix. These findings enhance our understanding of how single nucleotide mutations in transcription factor consensus sequences lead to dysfunctional transcription and, ultimately, human disease.

Transcriptional control of leukemogenesis by the chromatin reader SGF29

AbstractAberrant expression of stem cell–associated genes is a common feature in acute myeloid leukemia (AML) and is linked to leukemic self-renewal and therapy resistance. Using AF10-rearranged leukemia as a prototypical example of the recurrently activated “stemness” network in AML, we screened for chromatin regulators that sustain its expression. We deployed a CRISPR-Cas9 screen with a bespoke domain-focused library and identified several novel chromatin-modifying complexes as regulators of the TALE domain transcription factor MEIS1, a key leukemia stem cell (LSC)–associated gene. CRISPR droplet sequencing revealed that many of these MEIS1 regulators coordinately controlled the transcription of several AML oncogenes. In particular, we identified a novel role for the Tudor-domain–containing chromatin reader protein SGF29 in the transcription of AML oncogenes. Furthermore, SGF29 deletion impaired leukemogenesis in models representative of multiple AML subtypes in multiple AML subtype models. Our studies reveal a novel role for SGF29 as a nononcogenic dependency in AML and identify the SGF29 Tudor domain as an attractive target for drug discovery.

Meis1 establishes the pre-hemogenic endothelial state prior to Runx1 expression

Hematopoietic stem and progenitor cells (HSPCs) originate from an endothelial-to-hematopoietic transition (EHT) during embryogenesis. Characterization of early hemogenic endothelial (HE) cells is required to understand what drives hemogenic specification and to accurately define cells capable of undergoing EHT. Using Cellular Indexing of Transcriptomes and Epitopes by Sequencing (CITE-seq), we define the early subpopulation of pre-HE cells based on both surface markers and transcriptomes. We identify the transcription factor Meis1 as an essential regulator of hemogenic cell specification in the embryo prior to Runx1 expression. Meis1 is expressed at the earliest stages of EHT and distinguishes pre-HE cells primed towards the hemogenic trajectory from the arterial endothelial cells that continue towards a vascular fate. Endothelial-specific deletion of Meis1 impairs the formation of functional Runx1-expressing HE which significantly impedes the emergence of pre-HSPC via EHT. Our findings implicate Meis1 in a critical fate-determining step for establishing EHT potential in endothelial cells.

Responses in patients with AML and treated with entospletinib monotherapy.

e19010 Background: AML is a disease defined by the acquisition of genetic lesions in normal hematopoietic stem cells and progenitors resulting in poorly differentiated and highly proliferative leukemic blasts. Spleen tyrosine kinase (SYK) is a nonreceptor tyrosine kinase that maintains de-differentiation and leukemogenesis. MLL rearrangements (MLL-r) occur in up to 10% of adult AML and are associated with upregulated expression of the transcription factors HOXA9 and MEIS1 and worse clinical outcomes. Entospletinib (ENTO), an oral, selective inhibitor of SYK, has been studied in clinical trials for unselected AML patients as well as MLL-r patients. ENTO plus standard induction chemotherapy in front line had a 76% (13/17) composite complete response (CR) in AML patients with high HOXA9 and MEIS1. We have 3 patients that achieved CRs with ENTO monotherapy; one patient achieved CR to 14 days of ENTO monotherapy prior to initiation of chemotherapy; 2 patients with relapsed/refractory AML with MLL-r treated with ENTO monotherapy achieved CRs. Methods: This was part of an international multicenter phase Ib/II study (NCT02343939) which evaluated the efficacy, safety, and tolerability of ENTO in subjects with AML. During dose escalation, ENTO was administered in combination with induction chemotherapy (Group A) or with a hypomethylating agent (Group B). ENTO was administered as monotherapy for R/R AML in Group C. This report includes one patient from group A (newly diagnosed AML, MLL-r, 14-day monotherapy lead-in with ENTO) and two patients from group C monotherapy (relapsed/refractory AML, MLL-r). Results: Three patients receiving ENTO monotherapy had CRs. 18-year-old male from group A, that was MLL-r, NPM1-mutant (-). Patient treated at 400 mg PO, BID, achieved a cytogenetic CR with incomplete count recovery after cycle 0 (before chemotherapy); the patient continued study with induction chemotherapy and ultimately received ASCT in CR. Two additional patients in group C (with multiple therapies), both at 400 mg bid: (i) 37-year-old male, MLL-r, NPM1(-), was on study for 28 days, achieved CR; (ii) 28-year-old female, MLL-r, NPM1(-) on study for 60 days, achieved CR, both proceeded to SCT. Conclusions: Based on the results from these three patients, the clinical activity of SYK inhibition should be explored further in AML. We are testing Lanraplenib, a next-generation SYK inhibitor with enhanced selectivity, and more favorable pharmacologic properties in combination in genetically defined subsets of AML (NCT05028751). Clinical trial information: NCT02343939 .

Discovery of new tetrahydroisoquinolines as potent and selective LSD1 inhibitors for the treatment of MLL-rearranged leukemia

Histone lysine-specific demethylase 1 (LSD1) is a promising target for cancer therapy. Here, we performed the design, synthesis, and extensive structure-activity relationship (SAR) studies based on our previously discovered natural LSD1 inhibitor, higenamine. We found that the tetracyclic tetrahydroisoquinoline FY-21 is a potent and selective inhibitor of LSD1 (IC50 = 340 nM). FY-21 inhibited leukemia cell proliferation and colony formation and increased the level of p53 expression. Meanwhile, FY-21 reduced the mRNA levels of the transcription factors HOXA9 and MEIS1. Furthermore, FY-21 significantly induced leukemia cell differentiation. In vivo studies showed that FY-21 prolonged the survival rate of leukemia mice. Collectively, FY-21 is a potent, selective LSD1 inhibitor and can serve as a lead compound for the development of novel and highly effective LSD1 inhibitors for AML treatment.

MEIS1 Is a Common Transcription Repressor of the miR-23a and NORHA Axis in Granulosa Cells.

MicroRNA-23a (miR-23a) is an endogenous small activating RNA (saRNA) involved in ovarian granulosa cell (GC) apoptosis and sow fertility by activating lncRNA NORHA transcription. Here, we reported that both miR-23a and NORHA were repressed by a common transcription factor MEIS1, which forms a small network regulating sow GC apoptosis. We characterized the pig miR-23a core promoter, and the putative binding sites of 26 common transcription factors were detected in the core promoters of both miR-23a and NORHA. Of them, transcription factor MEIS1 expression was the highest in the ovary, and widely distributed in various ovarian cells, including GCs. Functionally, MEIS1 is involved in follicular atresia by inhibiting GC apoptosis. Luciferase reporter and ChIP assays showed that transcription factor MEIS1 represses the transcription activity of miR-23a and NORHA through direct binding to their core promoters. Furthermore, MEIS1 represses miR-23a and NORHA expression in GCs. Additionally, MEIS1 inhibits the expression of FoxO1, a downstream of the miR-23a/NORHA axis, and GC apoptosis by repressing the miR-23a/NORHA axis. Overall, our findings point to MEIS1 as a common transcription repressor of miR-23a and NORHA, and develop the miR-23a/NORHA axis into a small regulatory network regulating GC apoptosis and female fertility.

A Common Variant in GRK5 Reveals a PAR1-Specific Mechanism for Its Regulation of Platelet Function

Two separate genome wide association studies (GWAS), recently conducted by our group and another group, have identified the variant rs10886430 in the G protein-coupled receptor kinase 5 (GRK5) gene with a minor allele frequency of ~14% in Caucasians. Both studies show that the variant resides in a megakaryocyte-specific enhancer that alters the binding of the transcription factors GATA1 and MEIS1. In contrast to the major allele (A), the minor allele (G) is associated with decreased GRK5 mRNA expression, increased platelet reactivity, and greater risk of cardiovascular disease. However, the effect of the variant on protein expression has not been investigated by either group. In addition, there is an inconsistency between the findings of each of the studies regarding the specific role of GRK5 in thrombin receptor PAR1- and PAR4-mediated platelet activation. Further studies are needed to clarify whether, and how, GRK5 regulates platelet activity via PAR1, PAR4, or both. Here we introduce the A>G mutation into a megakaryoblastic cell line, Meg-01, by CRISPR-Cas9 genome editing. GRK5 protein expression is decreased by 80% in A>G mutant Meg-01 cells compared to WT control cells. To determine whether GRK5 regulates PAR1, PAR4, or both, we have isolated human platelets and specifically blocked GRK5 activity with compound CCG273261 to compare platelet responses to PAR1- and PAR4-specific agonists. Our data show that pharmacological inhibition of GRK5 increases markers of platelet activation such as integrin activation and P-selectin surface exposure in response to PAR1 receptor agonist peptide. Platelet activation in response to PAR4 receptor agonist peptide is normal. Furthermore, this inhibition increases Ca2+ mobilization in response to PAR1 receptor agonist, but not to PAR4 receptor agonist. Consistent with the results of our functional assays, mass spectrometry analysis revealed an interaction between GRK5 and PAR1 but did not detect an interaction with PAR4. Collectively, our data show that 1) this GRK5 intronic variant regulates GRK5 expression at both transcriptional and translational levels, 2) GRK5 preferentially regulates PAR-1 over PAR4-mediated signaling, and 3) GRK5 has a binding interaction with PAR1 (Fig 1). Our findings will enable us to develop superior therapeutics for cardiovascular risk groups especially those individuals who carry the intronic variant in GRK5 and as a result are more likely to experience thrombotic events. Figure 1View largeDownload PPTFigure 1View largeDownload PPT Close modal

Meis1 Regulates Nociceptor Development and Behavioral Response to Tactile Stimuli.

Nociceptors in the dorsal root ganglia (DRG) and trigeminal ganglia (TG) are necessary for transmitting pain and itch signals. However, the molecular mechanism regulating nociceptor development remains largely unknown. This study identifies that the transcription factor Meis1 is generally expressed in two groups of sensory neurons in the developing DRG. During prenatal and neonatal stages, approximately 2/3 of Meis1+ neurons are Runx1+ nociceptors, while 1/3 of Meis1+ neurons are NF200+ myelinated neurons. At postnatal stages, Meis1 expression in nociceptors is gradually reduced. Here, we constructed a Meis1 conditional knockout mouse line to selectively delete Meis1 in Nav1.8 lineage nociceptors. Microarray analyses showed that differentially expressed genes in the Meis1 mutant DRG were enriched in pathways related to sensory perception of pain and nervous system development. In addition, Meis1 regulates the expression of some marker genes of Nppb+ neurons and C-LTMRs. Furthermore, Meis1 mutant mice exhibit behavioral deficits in response to light mechanical pain, static touch and chemical itch. Therefore, this study reveals that Meis1 is required to regulate the development of nociceptors.

Meis1 supports leukemogenesis through stimulation of ribosomal biogenesis and Myc.

The homeobox transcription factors HoxA9 and Meis1 are causally involved in the etiology of acute myeloid leukemia. While HoxA9 alone immortalizes cells, cooperation with Meis1 is necessary to induce a full leukemic phenotype. Here, we applied degron techniques to elucidate the leukemogenic contribution of Meis1. Chromatin immunoprecipitation experiments revealed that Meis1 localized mainly to H3K27 acetylated and H3K4 mono-methylated enhancers preactivated by HoxA9. Chromatin association of Meis1 required physical presence of HoxA9 and all Meis1 DNA interactions were rapidly lost after HoxA9 degradation. Meis1 controlled a gene expression pattern dominated by Myc, ribosome biogenesis and ribosomal RNA synthesis genes. While Myc accounted for the cell cycle stimulating effect of Meis1, overexpression of this oncogene alone did not accelerate leukemogenesis. Besides its effect on Myc, Meis1 induced transcription of ribosomal biogenesis genes. This was accompanied by an elevated resistance against inhibition of ribosomal RNA synthesis and translation, but without affecting steady-state protein synthesis. Finally, we demonstrate that HoxA9 and Meis1 proteins are stabilized by post-translational modification. Mutation of HoxA9/Meis1 phosphorylation sites or inhibition of casein kinase 2 lead to rapid protein degradation suggesting a potential pathway for pharmacological intervention.

Homeodomain transcription factor MEIS1 as a novel player regulating hMSC-TERTs osteogenic differentiation

Homeodomain transcription factor MEIS1 as a novel player regulating hMSC-TERTs osteogenic differentiation

Discovery of natural product-like spirooxindole derivatives as highly potent and selective LSD1/KDM1A inhibitors for AML treatment

Histone lysine specific demethylase 1 (LSD1) is a promising new therapeutic target for cancer therapy. Following the work on the discovery of natural LSD1 inhibitor higenamine, we herein performed further structure-based design, synthesis, and extensive structure–activity relationship (SAR) studies, affording structurally new spirooxindole derivatives. Particularly, FY-56 was identified to be a highly potent LSD1 inhibitor (IC50 = 42 nM) and showed high selectivity over monoamine oxidases (MAO-A/B). Mechanistic studies showed that FY-56 moderately inhibited the proliferation and clone formation of leukemia cells, induced H3K4me1/2 accumulation and p53 activation as well as reduced the mRNA levels of the transcription factors HOXA9 and MEIS1. Meanwhile, FY-56 induced differentiation of MOLM-13 and MV4-11 cells, accompanied by an enhanced percentage of markers characteristic to differentiated macrophages and monocytes. Further in vivo studies showed that FY-56 obviously reduced the proportion of CD45+/CD33+ leukocytes in peripheral blood and spleen, and significantly prolonged the survival rate of mice. Collectively, FY-56 represents a structurally novel, highly potent and selective LSD1 inhibitor and exhibits therapeutic promise for AML treatment. The spirooxindole scaffold derived from FY-56 could be used to design structurally new LSD1 inhibitors for treating human diseases.

Transcription factor Meis1 act as a new regulator of ischemic arrhythmias in mice

IntroductionThe principal voltage-gated Na+ channel, NaV1.5 governs heart excitability and conduction. NaV1.5 dysregulation is responsible for ventricular arrhythmias and subsequent sudden cardiac death (SCD) in post-infarct hearts. The transcription factor Meis1 performs a significant role in determining differentiation fate and regenerative capability of cardiomyocytes. However, the functions of Meis1 in ischemic arrhythmias following myocardial infarction (MI) are still largely undefined. ObjectivesHere we aimed to study whether Meis1 could act as a key regulator to mediate cardiac Na+ channel and its underlying mechanisms. MethodsHeart-specific Meis1 overexpression was established by AAV9 virus injection in C57BL/6 mice. The QRS duration, the incidence of ventricular arrhythmias and cardiac conduction velocity were evaluated by ECG, programmed electrical stimulation and optical mapping techniques respectively. The conventional patch clamp technique was performed to explore the INa characteristics of isolated mouse ventricular myocytes. In vitro, Meis1 was also overexpressed in hypoxic-treated neonatal cardiomyocytes. The analysis of immunoblotting and immunofluorescence were used to detect the changes in the expression of NaV1.5 in each group. ResultsWe found that forced expression of Meis1 rescued the prolongation of QRS complex, produced anti-arrhythmic activity and improved epicardial conduction velocity in infarcted mouse hearts. In terms of mechanisms, cardiac electrophysiological changes of MI mice can be ameliorated by the recovery of Meis1, which is characterized by the restoration of INa current density and NaV1.5 expression level of cardiomyocytes in the marginal zone of MI mouse hearts. Furthermore, in vitro studies showed that Meis1 was also able to rescue hypoxia-induced decreased expression and dysfunction of NaV1.5 in ventricular myocytes. We further revealed that E3 ubiquitin ligase CDC20 led to the ubiquitination and degradation of Meis1, which blocked the transcriptional regulation of SCN5A by Meis1 and ultimately led to the electrophysiological remodeling in ischemic-hypoxic cardiomyocytes. ConclusionCDC20 mediates ubiquitination of Meis1 to govern the transcription of SCN5A and cardiac electrical conduction in mouse cardiomyocytes. This finding uncovers a new mechanism of NaV1.5 dysregulation in infarcted heart, and provides new therapeutic strategies for malignant arrhythmias and sudden cardiac death following MI.

G protein–coupled receptor kinase 5 regulates thrombin signaling in platelets via PAR-1

AbstractThe interindividual variation in the functional response of platelets to activation by agonists is heritable. Genome-wide association studies (GWASs) of quantitative measures of platelet function have identified fewer than 20 distinctly associated variants, some with unknown mechanisms. Here, we report GWASs of pathway-specific functional responses to agonism by adenosine 5′-diphosphate, a glycoprotein VI–specific collagen mimetic, and thrombin receptor-agonist peptides, each specific to 1 of the G protein–coupled receptors PAR-1 and PAR-4, in subsets of 1562 individuals. We identified an association (P = 2.75 × 10−40) between a common intronic variant, rs10886430, in the G protein–coupled receptor kinase 5 gene (GRK5) and the sensitivity of platelets to activate through PAR-1. The variant resides in a megakaryocyte-specific enhancer that is bound by the transcription factors GATA1 and MEIS1. The minor allele (G) is associated with fewer GRK5 transcripts in platelets and the greater sensitivity of platelets to activate through PAR-1. We show that thrombin-mediated activation of human platelets causes binding of GRK5 to PAR-1 and that deletion of the mouse homolog Grk5 enhances thrombin-induced platelet activation sensitivity and increases platelet accumulation at the site of vascular injury. This corroborates evidence that the human G allele of rs10886430 is associated with a greater risk for cardiovascular disease. In summary, by combining the results of pathway-specific GWASs and expression quantitative trait locus studies in humans with the results from platelet function studies in Grk5−/− mice, we obtain evidence that GRK5 regulates the human platelet response to thrombin via the PAR-1 pathway.

Control of mouse limb initiation and antero-posterior patterning by Meis transcription factors

Meis1 and Meis2 are homeodomain transcription factors that regulate organogenesis through cooperation with Hox proteins. Elimination of Meis genes after limb induction has shown their role in limb proximo-distal patterning; however, limb development in the complete absence of Meis function has not been studied. Here, we report that Meis1/2 inactivation in the lateral plate mesoderm of mouse embryos leads to limb agenesis. Meis and Tbx factors converge in this function, extensively co-binding with Tbx to genomic sites and co-regulating enhancers of Fgf10, a critical factor in limb initiation. Limbs with three deleted Meis alleles show proximal-specific skeletal hypoplasia and agenesis of posterior skeletal elements. This failure in posterior specification results from an early role of Meis factors in establishing the limb antero-posterior prepattern required for Shh activation. Our results demonstrate roles for Meis transcription factors in early limb development and identify their involvement in previously undescribed interaction networks that regulate organogenesis.

MEIS-WNT5A axis regulates development of fourth ventricle choroid plexus.

The choroid plexus (ChP) produces cerebrospinal fluid and forms an essential brain barrier. ChP tissues form in each brain ventricle, each one adopting a distinct shape, but remarkably little is known about the mechanisms underlying ChP development. Here, we show that epithelial WNT5A is crucial for determining fourth ventricle (4V) ChP morphogenesis and size in mouse. Systemic Wnt5a knockout, or forced Wnt5a overexpression beginning at embryonic day 10.5, profoundly reduced ChP size and development. However, Wnt5a expression was enriched in Foxj1-positive epithelial cells of 4V ChP plexus, and its conditional deletion in these cells affected the branched, villous morphology of the 4V ChP. We found that WNT5A was enriched in epithelial cells localized to the distal tips of 4V ChP villi, where WNT5A acted locally to activate non-canonical WNT signaling via ROR1 and ROR2 receptors. During 4V ChP development, MEIS1 bound to the proximal Wnt5a promoter, and gain- and loss-of-function approaches demonstrated that MEIS1 regulated Wnt5a expression. Collectively, our findings demonstrate a dual function of WNT5A in ChP development and identify MEIS transcription factors as upstream regulators of Wnt5a in the 4V ChP epithelium.

Meis homeobox genes control progenitor competence in the retina

The vertebrate eye is derived from the neuroepithelium, surface ectoderm, and extracellular mesenchyme. The neuroepithelium forms an optic cup in which the spatial separation of three domains is established, namely, the region of multipotent retinal progenitor cells (RPCs), the ciliary margin zone (CMZ)-which possesses both a neurogenic and nonneurogenic potential-and the optic disk (OD), the interface between the optic stalk and the neuroretina. Here, we show by genetic ablation in the developing optic cup that Meis1 and Meis2 homeobox genes function redundantly to maintain the retinal progenitor pool while they simultaneously suppress the expression of genes characteristic of CMZ and OD fates. Furthermore, we demonstrate that Meis transcription factors bind regulatory regions of RPC-, CMZ-, and OD-specific genes, thus providing a mechanistic insight into the Meis-dependent gene regulatory network. Our work uncovers the essential role of Meis1 and Meis2 as regulators of cell fate competence, which organize spatial territories in the vertebrate eye.

Transcription Factor Meis1 Act As a New Regulator Of Ischemic Arrhythmias In Mice

Background: The principal voltage-gated Nam+ channel, NaV1.5 governs heart excitability and conduction. NaV1.5 dysregulation is responsible for ventricular arrhythmias and subsequent sudden cardiac death in post-infarct hearts. The transcription factor Meis1 plays an important role in determining differentiation fate and regenerative capability of cardiomyocytes. However, the functions of Meis1 in ischemic arrhythmias following myocardial infarction (MI) are still largely undefined. Here we set out to study whether Meis1 could act as a key regulator to mediate cardiac Na+ channels and arrhythmogenesis and its underlying mechanisms. Methods: Heart-specific Meis1 overexpression was established by AAV9 virus injection in C57BL/6 mice. The QTc interval, the incidence of ventricular arrhythmias and cardiac conduction velocity were evaluated by ECG, programmed electrical stimulation and optical mapping techniques respectively. The conventional patch clamp technique was used to study the I Na characteristics of isolated mouse ventricular myocytes. Findings: We found that forced expression of Meis1 rescued the prolongation of heart rate corrected QT (QTc) interval, produced anti-arrhythmic activity and improved epicardial conduction velocity in infarcted mouse hearts. Mechanistically, Meis1 may ameliorate cardiac electrophysiological remodeling as characterized by the decrease of INa current density and NaV1.5 expression in marginal zone of infarcted mouse hearts. Furthermore, in vitro studies showed that E3 ubiquitin ligase CDC20 led to the ubiquitination and degradation of Meis1, which blocked the transcriptional regulation of SCN5A. Interpretation: This study demonstrates that Meis1 overexpression can effectively inhibit the ventricular arrhythmia by regulating the transcription of SCN5A and cardiac electrical conductance in mouse ischemic heart, which provides new therapeutic strategies for malignant arrhythmias and sudden cardiac death following MI. Funding: This work was supported by the National Nature Science Foundation of China [Grant No. 81573425 and 81773733 to NW]. Declaration of Interest: None to declare. Ethical Approval: All animal experiments were performed along with the NIH guidelines (Guide for the care and use of laboratory animals, NIH Publication No. 85-23, revised 1996) and were conducted in accordance with the protocols approved by the Institutional Animal Care and Use Committee of Harbin Medical University.

Homeobox transcription factor Meis1 is crucial to Sertoli cell mediated regulation of male fertility.

Infertility has become a global phenomenon and constantly declining sperm count in males in modern world pose a major threat to procreation of humans. Male fertility is critically dependent on proper functioning of testicular Sertoli cells. Defective Sertoli cell proliferation and/or impaired functional maturation may be one of the underlying causes of idiopathic male infertility. Using high-throughput "omics" approach, wefoundbinding sites for homeobox transcription factor MEIS1 on the promoters of several genes up-regulated in pubertal (mature) Sertoli cells, indicating that MEIS1 may becrucialfor Sertoli cell-mediated regulation of spermatogenesis at and after puberty. To decipher the role of transcription factor MEIS1 in Sertoli cell maturation and spermatogenesis. Sc-specific Meis1 knockdown (KD) transgenic mice were generated using pronuclear microinjection. Morphometric and histological analysis of the testes from transgenic mice was performed to identify defects in spermatogenesis. Epididymal sperm count and litter size were analyzed to determine the effect of Meis1 knockdown on fertility. Sertoli cell (Sc)-specific Meis1 KD led to massive germ cell loss due to apoptosis and impaired spermatogenesis. Unlike normal pubertal Sc, the levels of SOX9 in pubertal Sc of Meis1 KD were significantly high, like immature Sc. A significant reduction in epididymal sperm count was observed in these mice. The mice were found to be infertile or sub-fertile (with reduced litter size), depending on the extent of Meis1 inhibition. The results of this study demonstrated for the first time, a role of Meis1 in Sc maturation and normal spermatogenic progression. Inhibition of Meis1 in Sc was associated with deregulated spermatogenesis and a consequent decline in fertility of the transgenic mice. Our results provided substantial evidence that suboptimal Meis1 expression in Sc may be one of the underlying causes of idiopathic infertility.

Homeodomain transcription factor MEIS1 inhibits differentiation of immortalised human MSCs

Homeodomain transcription factor MEIS1 inhibits differentiation of immortalised human MSCs

Proximo-distal positional information encoded by an Fgf-regulated gradient of homeodomain transcription factors in the vertebrate limb.

The positional information theory proposes that a coordinate system provides information to embryonic cells about their position and orientation along a patterning axis. Cells interpret this information to produce the appropriate pattern. During development, morphogens and interpreter transcription factors provide this information. We report a gradient of Meis homeodomain transcription factors along the mouse limb bud proximo-distal (PD) axis antiparallel to and shaped by the inhibitory action of distal fibroblast growth factor (FGF). Elimination of Meis results in premature limb distalization and HoxA expression, proximalization of PD segmental borders, and phocomelia. Our results show that Meis transcription factors interpret FGF signaling to convey positional information along the limb bud PD axis. These findings establish a new model for the generation of PD identities in the vertebrate limb and provide a molecular basis for the interpretation of FGF signal gradients during axial patterning.