Giovanni Levi

Muséum National d'Histoire Naturelle · UMR CNRS / MNHN 7221 : Evolution des régulations endocriniennes

Skeletal shape and mechanical properties define, to a large extent, vertebrate morphology and physical capacities. During development, skeletal morphogenesis results from dynamic communications between chondrocytes, osteoblasts, osteoclasts, and other cellular components of the skeleton. Later in life, skeletal integrity depends on the regulatory c...

Dlx5 and Dlx6 encode distal-less homeodomain transcription factors that are present in the genome as a linked pair at a single locus. Dlx5 and Dlx6 have redundant roles in craniofacial, skeletal, and uterine development. Previously, we performed a transcriptome comparison for anti-Müllerian hormone (AMH)-induced genes expressed in the Müllerian duc...

Neuronal circuits integrating Parvalbumin-positive GABAergic inhibitory interneurons (PV) are essential for normal brain function and are often altered in psychiatric conditions. During development, Dlx5 and Dlx6 (Dlx5/6) genes are involved in the differentiation of PV-interneurons. In the adult, Dlx5/6 continue to be expressed at low levels in mos...

Dlx5 and Dlx6 encode distal-less homeodomain transcription factors that are present in the genome as a linked pair at a single locus. Dlx5 and Dlx6 have redundant roles in craniofacial, skeletal, and uterine development. Previously, we performed a transcriptome comparison for anti-Mullerian hormone (AMH)-induced genes expressed in the Mullerian duc...

DLX5 and DLX6 are two closely related transcription factors involved in brain development and in GABAergic differentiation. The DLX5/6 locus is regulated by FoxP2, a gene involved in language evolution and has been associated to neurodevelopmental disorders and mental retardation. Targeted inactivation of Dlx5/6 in mouse GABAergic neurons (Dlx5/6Vg...

DLX5 and DLX6 are two closely related transcription factors involved in brain development and in GABAergic differentiation. The DLX5/6 locus is regulated by FoxP2, a gene involved in language evolution and has been associated to neurodevelopmental disorders and mental retardation. Targeted inactivation of Dlx5/6 in mouse GABAergic neurons ( Dlx5/6...

Dlx5 and Dlx6 encode two homeobox transcription factors expressed by developing and mature GABAergic interneurons. During development, Dlx5/6 play a role in the differentiation of certain GABAergic subclasses. Here we address the question of the functional role of Dlx5/6 in the mature central nervous system. First, we demonstrate that Dlx5 and Dlx6...

Background Osteoporosis which affects 200 million women worldwide is the consequence of an imbalance of low anabolism to high catabolism, causing a risk of fracture. Impaired anabolism involved reduced osteoblast differentiation. The osteoblast differentiation is mediated by transcription factors, including Dlx5 and Dlx6. Dlx5 is known to have a ro...

Dlx5 and Dlx6 encode two homeobox transcription factors expressed by developing and mature GABAergic interneurons. During development Dlx5/6 are important for the differentiation of Parvalbumin ( Pvalb )-expressing neurons. Perinatal lethality of homozygous mice in which Dlx5/6 have been constitutively deleted has, so far, hindered the study of the...

Neural tube defects (NTDs), one of the most common birth defects in human, present a multifactorial etiology with a poorly defined genetic component. The Dlx5 and Dlx6 bigenic cluster encodes two evolutionary conserved homeodomain transcription factors, which are necessary for proper vertebrate development. It has been shown that Dlx5/6 genes are e...

Expression of fgf8a, shha and bmp4 during zebrafish posterior neurulation. (A-H) Lateral views of whole-mount in situ hybridization in controls (injected with water) and dlx5a/6a zebrafish morphants for fgf8a at 16 hpf (A-B), shha at 24 hpf and 48 hpf (C-F) and for bmp4 at 48 hpf (G-H) (n>8 for each condition). The inactivation of dlx5a/6a leads to...

Dlx5 expression after posterior neuropore closure in mouse. (A, B) Lateral views of whole-mount in situ hybridization for Dlx5 in E10.5 and E12.5 mice. The dashed lines indicate the section levels analysed in Fig 3G and 3H. Dlx5 expression is detected at the cloacal level and in the VER at E10.5 (A, blue and grey arrowheads respectively) but is not...

Phenotypes resulting from the morpholino knockdown and mRNA rescue experiments. Proportion of normal (blue), moderate (purple) and severe (red) phenotypes observed at 48 hpf after morpholino knockdown and mRNA rescue experiments. The number (n) of specimens analysed is indicated for each treatment. Treatments: control embryos injected with H2O; con...

Defect of neuromuscular innervation in Dlx5/6-/- mice. (A-B) Immunostaining on coronal cryosections for Tnnt3 and Tuj1 in epaxial muscles of E18.5 control and Dlx5/6-/- foetuses (n = 3 for each condition). The Dlx5/6-/- mutants show defect of neuromuscular innervation in epaxial musculature. Abbreviations: epm, epaxial muscles. Scale bar in A for A...

Gnathostome jaws derive from the first pharyngeal arch (PA1), a complex structure constituted by Neural Crest Cells (NCCs), mesodermal, ectodermal and endodermal cells. Here, to determine the regionalized morphogenetic impact of Dlx5/6 expression, we specifically target their inactivation or overexpression to NCCs. NCC-specific Dlx5/6 inactivation...

Neural tube defects (NTDs), one of the most common birth defects in human, present a multifactorial etiology with a poorly defined genetic component. The Dlx5 and Dlx6 bigenic cluster encodes two evolutionary conserved homeodomain transcription factors, which are necessary for proper vertebrate development. It has been shown that Dlx5/6 genes are e...

Gnathostome jaws derive from the first pharyngeal arch (PA1), a complex structure constituted by Neural Crest Cells (NCCs), mesodermal, ectodermal and endodermal cells. Here, to determine the regionalized morphogenetic impact of Dlx5/6 expression, we specifically target their inactivation or overexpression to NCCs. NCC-specific Dlx5/6 inactivation...

Background It has been repetitively shown that the transcription factors DLX5 and DLX6 are drastically downregulated in endometriotic lesions when compared with eutopic endometrium. These findings suggest that regulatory cascades involving DLX5/6 might be at the origin of endometriosis symptoms such as chronic pelvic pain (CPP). We have shown that...

Capsule Comparative analysis of gene expression signatures from endometriosis and mouse models shows that CACNAα2δs calcium-channel components involved in nociception are targets for the treatment of endometriosis-associated pain. Context Differential gene expression analyses comparing endometriotic lesions to eutopic endometrium have shown that t...

Background Preeclampsia is a complex and common human-specific pregnancy syndrome associated with placental pathology. The human specificity provides both intellectual and methodological challenges, lacking a robust model system. Given the role of imprinted genes in human placentation and the vulnerability of imprinted genes to loss of imprinting c...

Objectif Les gènes codant pour les facteurs de transcriptions DLX5 et DLX6 sont fortement sous-exprimés au sein des lésions d’endométriose par rapport à l’endomètre normal (Hawkins et al., 2011, Hever et al., 2007, Hu et al., 2006). Nous avons montré qu’une inactivation dans l’utérus de Dlx5 et Dlx6 chez la souris aboutit à une histologie similaire...

Dlx5 and Dlx6 are two closely associated homeobox genes which code for transcription factors involved in the control of steroidogenesis and reproduction. Inactivation of Dlx5/6 in the mouse results in a Leydig cell defect in the male and in ovarian insufficiency in the female. DLX5/6 are also strongly expressed by the human endometrium but their fu...

Contexte Dlx5 et Dlx6 sont deux facteurs de transcription qui jouent un role important dans le controle de la morphogenese et la differenciation cellulaire. Des donnees preliminaires ont montre la presence de ces facteurs dans l’uterus chez la souris. Objectifs Etude de Dlx5 et Dlx6 au cours du developpement de l’uterus chez la souris. Materiel et...

The amniote middle ear is a classical example of the evolutionary novelty. Although paleontological evidence supports the view that mammals and diapsids (modern reptiles and birds) independently acquired the middle ear after divergence from their common ancestor, the developmental bases of these transformations remain unknown. Here we show that low...

Most gnathostomata craniofacial structures derive from pharyngeal arches (PAs), which are colonized by cranial neural crest cells (CNCCs). The anteroposterior and dorsoventral identities of CNCCs are defined by the combinatorial expression of Hox and Dlx genes. The mechanisms associating characteristic Hox/Dlx expression patterns with the topology...

Foxl2 codes for a forkhead/HNF3 transcription factor essential for follicular maturation and maintenance of ovarian identity. FOXL2 mutations are associated with Blepharophimosis, Ptosis, and Epicanthus inversus Syndrome (BPES) characterized by eyelid malformations (type I and II) and premature ovarian insufficiency (type I). We show that Foxl2 is...

Blepharophimosis, ptosis, epicanthus-inversus syndrome (BPES) is an autosomal dominant genetic disorder characterized by narrow palpebral fissures and eyelid levator muscle defects. BPES is often associated to premature ovarian insufficiency (BPES type I). FOXL2, a member of the forkhead transcription factor family, is the only gene known to be mut...

Asymmetric, articulated jaws are characteristic of most vertebrate species; they derive from the first pharyngeal arch (PA1) which generates both maxillary and mandibular components. PA1 is colonized by cranial neural crest cells (CNCCs) which give rise to most bones and tendons of the jaws. The elements formed by different CNCCs contingents are sp...

Cell death and differentiation is a monthly research journal focused on the exciting field of programmed cell death and apoptosis. It provides a single accessible source of information for both scientists and clinicians, keeping them up-to-date with advances in the field. It encompasses programmed cell death, cell death induced by toxic agents, dif...

Asymmetric, articulated jaws are characteristic of most vertebrate species; they derive from the first pharyngeal arch (PA1) which generates both maxillary and mandibular components. PA1 is colonized by cranial neural crest cells (CNCCs) which give rise to most bones and tendons of the jaws. The elements formed by different CNCCs contingents are sp...

At least 10% of the Sebitoli chimpanzee community of the Kibale National Park (Uganda) present a characteristic facial phenotype with flattened nose, reduced nostrils, and concave mid-face. Affected individuals do not present skin lesions, and also young infants are affected. We suggest, therefore, a congenital origin of this defect.

DLX5 belongs to the six-member family of DLX genes characterized by a homeobox related to that found in the insect Distal-less (Dll) gene. The six DLX genes are organized as three bigenic pairs with a tail-to-tail orientation (Zerucha et al., 2000) and located on chromosomes where HOX clusters are also found (DLX5/DLX6; 7q21.3, syntenic to the HOXA...

DLX6 belongs to the six-member family of DLX genes characterized by a homeobox related to that found in the insect Distal-less (Dll) gene. The six DLX genes are organized as three bigenic pairs with a tail-to-tail orientation (Zerucha et al., 2000), and located on chromosomes where HOX clusters are also found (DLX5/DLX6; 7q21.3, syntenic to the HOX...

DLX2 belongs to the six-member family of DLX genes characterized by a homeobox related to that found in the insect Distal-less (Dll) gene. It was the first human homologue to be discovered (Selski et al., 1993; McGuinness et al., 1996). The six DLX genes are organized as three bigenic pairs with a tail-to-tail orientation (Zerucha et al., 2000) and...

Asymmetric, articulated jaws support active predation in vertebrates; they derive from the first pharyngeal arch (PA1) which generates both maxillary and mandibular components. PA1 is colonized by cranial neural crest cells (CNCCs) which give rise to most bones and tendons of the jaws. The elements formed by different CNCCs contingents are specifie...

Endothelin-1 (Edn1), originally identified as a vasoconstrictor peptide, is involved in the development of cranial/cardiac neural crest-derived tissues and organs. In craniofacial development, Edn1 binds to Endothelin type-A receptor (Ednra) to induce homeobox genes Dlx5/Dlx6 and determines the mandibular identity in the first pharyngeal arch. Howe...

The Dlx and Msx homeodomain transcription factors play important roles in the control of limb development. The combined disruption of Msx1 and Msx2, as well as that of Dlx5 and Dlx6, lead to limb patterning defects with anomalies in digit number and shape. Msx1;Msx2 double mutants are characterized by the loss of derivatives of the anterior limb me...

Top. Location of predicted conserved Dlx binding sites in the Dlx5-Dlx6 intergenic genomic region. Sites are indicated with colour vertical bars (asterisk) and annotated with the species conservation. The chromosomal position and coordinates are also reported. The mammalian genomic conservation is reported on the bottom. The known i56i element is c...

Sequences of the mouse and human conserved genomic regions containing predicted Dlx5 binding sites near the BMP2 locus. (PDF)

Quantification of the Msx2 mRNAs by qRT-PCR in the anterior and posterior halves of HLs from Msx1+/−;Dlx5−/−;Dlx6−/− embryos, relative to the corresponding WT samples (set = 1). (PDF)

Quantification of the Fgf8 and Shh mRNAs by qRT-PCR in the HLs from Msx1−/− (top left), Dlx5−/−;Dlx6−/− (top right), Msx1+/−;Dlx5+/−;Dlx6+/− (bottom left) and Msx1+/−;Dlx5−/−;Dlx6−/− (bottom right) embryos, relative to the corresponding WT samples (set = 1). (PDF)

The Dlx5 Position-Weight matrix and results of the prediction of Dlx5 binding sites based on genomic conservation. (PDF)

Sequences of the oligonucleotides used for real-time qPCR on mouse embryonic tissues. (PDF)

Sequences of the mouse and human conserved genomic regions containing predicted Dlx5 binding sites near the BMP4 locus. (PDF)

Sequences of the oligonucleotides used for ChIP analysis on the predicted Dlx elements near the human BMP2 and BMP4 loci. (PDF)

The human condition known as Premature Ovarian Failure (POF) is characterized by loss of ovarian function before the age of 40. A majority of POF cases are sporadic, but 10-15% are familial, suggesting a genetic origin of the disease. Although several causal mutations have been identified, the etiology of POF is still unknown for about 90% of the p...

Primers and conditions of PCR used for sequencing SHFM1, DLX5 and DLX6 . (DOC)

List of genes present in the loci identified on chromosomes 7 and 13 by genome-wide linkage in the MO1 POF family. The lists were established using the NCBI Genome Viewer, using the rs number of the border SNPs, as given in Table 1. Pseudogenes are written in grey. (XLS)

First arch syndromes correspond to a wide spectrum of human latero-facial congenital anomalies affecting cranial neural crest cells (CNCCs) derivatives of the first pharyngeal arch (PA1). The abnormal traits display variable quantitative expression and are often unilateral. Mandibular skeletal defects are invariably accompanied by hypoplasia or age...

Primary ovarian insufficiency (POI) is characterized by the loss of ovarian function before the age of 40 in humans. Although most cases of POI are idiopathic, many are familial, underlying a genetic origin of the disease. Mutations in genes involved in the control of steroidogenesis, such as NR5A1 (SF-1, Steroidogenic Factor 1), CYP17, CYP19A1 (ar...

Morphogenesis of the vertebrate facial skeleton depends upon inductive interactions between cephalic neural crest cells (CNCCs) and cephalic epithelia. The nasal capsule is a CNCC-derived cartilaginous structure comprising a ventral midline bar (mesethmoid) overlaid by a dorsal capsule (ectethmoid). Although Shh signalling from the anterior-most re...

Jaws are formed by cephalic neural crest (CNCCs) and mesodermal cells migrating to the first pharyngeal arch (PA1). A complex signaling network involving different PA1 components then establishes the jaw morphogenetic program. To gather insight on this developmental process, in this study, we analyze the teratogenic effects of brief (1-15 min) puls...

The DLX gene family encodes for homeobox transcription factors involved in the control of morphogenesis and tissue homeostasis. Their expression can be regulated by Endothelin1 (ET1), a peptide associated with breast cancer invasive phenotype. Deregulation of DLX gene expression was found in human solid tumors and hematologic malignancies. In parti...

The origin of active predation in vertebrates is associated with the rise of three major, uniquely derived developmental characteristics of the head: (i) migratory cranial neural crest cells (CNCCs) giving rise to most skeletal skull elements; (ii) expression of Dlx genes by CNCCs in the Hox-free first pharyngeal arch (PA1); and (iii) muscularizati...

The morphogenesis of the vertebrate skull results from highly dynamic integrated processes involving the exchange of signals between the ectoderm, the endoderm, and cephalic neural crest cells (CNCCs). Before migration CNCCs are not committed to form any specific skull element, molecular signals exchanged in restricted regions of tissue interaction...

The shaping of the vertebrate head results from highly dynamic integrated processes involving the growth and exchange of signals between the ectoderm, the endoderm, the mesoderm and Cephalic Neural Crest Cells (CNCCs). During embryonic development, these tissues change their shape and relative position rapidly and come transiently in contact with e...

Distal-less (Dlx) homeobox transcription factors play a central role in the control of osteogenesis. In particular, Dlx5 regulates osteoblasts/osteoclasts coupling during perinatal bone formation. We analyze here the effect of Dlx5 allelic reduction in the control of bone remodeling. We first show that Dlx5 expression persists during postnatal bone...

Understanding and manipulating gene function in physiological conditions is a major objective for both fundamental and applied research. In contrast to other experimental settings, which use either purely genetic or gene delivery (viral or non-viral) strategies, we report here a strategy based on direct protein delivery to central nervous system (C...

Explant preparation and exposure to protein conjugates. A) Lateral view of the brain removed from the head of an E13.5 embryo, to dissect out explants from the telencephalon (Tel) or spinal cord (Sc), in the areas delineated in red. B) Dorsal view of an adult brain, used to dissect out explants from the cerebral cortex (Ctx) or cerebellum (Cb), in...

Fusion to CPPs preserved Cre recombinase activity in both cell-free and cellular context. (A) Structure and SDS-PAGE electrophoretic profile using Sypro staining of the bacterially-produced fusion proteins, collectively designated as 'CPP-Cre' in this report. Peptidic additions did not significantly affect the apparent Mr of the Cre recombinase. Th...

Lack of transgene expression in Cre-reporter explants from different strains upon exposure to vehicle solution. (A-D) Detection of reporter gene expression within explants upon Cre transduction in similar conditions to those illustrated in the Fig. 2 drop assay. Vehicle-treated explant lack recombinant positive cells (A, B, D: R26R; C: Dbx1-DTA). (...

Cre reporter activity in CV1 cells upon plasmidic transfection and proteic transduction by CPP-Cre constructs. Expression of the constructs encoding the fusion proteins resulted in nuclear accumulation of the Cre conjugates (A), and nuclear β-Galactosidase reporter expression (B) in CV1B reporter cells. Eukaryotic versions of the plasmidic DNAs wer...

CPP-Cre conjugates induced similar recombination levels in drop transduction assays. Semi-quantification of the density of reporter-expressing cells in explants from four transgenic lines upon exposure to a 1 μl drop of indicated conjugates. 'Activity' is an index of mean recombination efficiency. Levels were documented by ascribing a qualitative a...