A spatio-temporally constrained gene regulatory network directed by PBX1/2 acquires limb patterning specificity via HAND2.

A lingering question in developmental biology has centered on how transcription factors with widespread distribution in vertebrate embryos can perform tissue-specific functions. Here, using the murine hindlimb as a model, we investigate the elusive mechanisms whereby PBX TALE homeoproteins, viewed primarily as HOX cofactors, attain context-specific developmental roles despite ubiquitous presence in the embryo. We first demonstrate that mesenchymal-specific loss of PBX1/2 or the transcriptional regulator HAND2 generates similar limb phenotypes.

Spatial and Quantitative Detection of BMP Activity in Mouse Embryonic Limb Buds.

Modulation of bone morphogenetic protein (BMP) activity is essential to the progression of limb development in the mouse embryo. Genetic disruption of BMP signaling at various stages of limb development causes defects ranging from complete limb agenesis to oligodactyly, polydactyly, webbing, and chondrodysplasia. To probe the state of BMP signaling in early limb buds, we designed two sets of primers to measure both spatially and quantitatively the transcription of nine key genes indicative of canonical BMP activity.

Cellular heterogeneity in the ureteric progenitor niche and distinct profiles of branching morphogenesis in organ development.

Branching morphogenesis creates arborized epithelial networks. In the mammalian kidney, an epithelial progenitor pool at ureteric branch tips (UBTs) creates the urine-transporting collecting system. Using region-specific mouse reporter strains, we performed an RNA-seq screen, identifying tip- and stalk-enriched gene sets in the developing collecting duct system.

Differential regulation of mouse and human nephron progenitors by the Six family of transcriptional regulators.

Nephron endowment is determined by the self-renewal and induction of a nephron progenitor pool established at the onset of kidney development. In the mouse, the related transcriptional regulators Six1 and Six2 play non-overlapping roles in nephron progenitors. Transient Six1 activity prefigures, and is essential for, active nephrogenesis.

ESCRT-II/Vps25 constrains digit number by endosome-mediated selective modulation of FGF-SHH signaling.

Sorting and degradation of receptors and associated signaling molecules maintain homeostasis of conserved signaling pathways during cell specification and tissue development. Yet, whether machineries that sort signaling proteins act preferentially on different receptors and ligands in different contexts remains mysterious. Here, we show that Vacuolar protein sorting 25, Vps25, a component of ESCRT-II (Endosomal Sorting Complex Required for Transport II), directs preferential endosome-mediated modulation of FGF signaling in limbs.

Dual requirement of ectodermal Smad4 during AER formation and termination of feedback signaling in mouse limb buds.

BMP signaling is pivotal for normal limb bud development in vertebrate embryos and genetic analysis of receptors and ligands in the mouse revealed their requirement in both mesenchymal and ectodermal limb bud compartments. In this study, we genetically assessed the potential essential functions of SMAD4, a mediator of canonical BMP/TGFß signal transduction, in the mouse limb bud ectoderm. Msx2-Cre was used to conditionally inactivate Smad4 in the ectoderm of fore- and hindlimb buds.

Smad4 is required to induce digit ray primordia and to initiate the aggregation and differentiation of chondrogenic progenitors in mouse limb buds.

SMAD4 is an essential mediator of canonical TGFβ/BMP signal transduction and we inactivated Smad4 in mouse limb buds from early stages onward to study its functions in the mesenchyme. While this Smad4 inactivation did not alter the early Sox9 distribution, prefiguring the chondrogenic primordia of the stylopod and zeugopod, it disrupted formation of all Sox9-positive digit ray primordia. Specific inactivation of Smad4 during handplate development pointed to its differential requirement for posterior and anterior digit ray primordia.

Distinct roles of Hand2 in initiating polarity and posterior Shh expression during the onset of mouse limb bud development.

The polarization of nascent embryonic fields and the endowment of cells with organizer properties are key to initiation of vertebrate organogenesis. One such event is antero-posterior (AP) polarization of early limb buds and activation of morphogenetic Sonic Hedgehog (SHH) signaling in the posterior mesenchyme, which in turn promotes outgrowth and specifies the pentadactylous autopod. Inactivation of the Hand2 transcriptional regulator from the onset of mouse forelimb bud development disrupts establishment of posterior identity and Shh expression, which results in a skeletal phenotype identical to Shh deficient limb buds.

Vertebrate limb development: moving from classical morphogen gradients to an integrated 4-dimensional patterning system.

A wealth of classical embryological manipulation experiments taking mainly advantage of the chicken limb buds identified the apical ectodermal ridge (AER) and the zone of polarizing activity (ZPA) as the respective ectodermal and mesenchymal key signaling centers coordinating proximodistal (PD) and anteroposterior (AP) limb axis development. These experiments inspired Wolpert's French flag model, which is a classic among morphogen gradient models. Subsequent molecular and genetic analysis in the mouse identified retinoic acid as proximal signal, and fibroblast growth factors (FGFs) and sonic hedgehog (SHH) as the essential instructive signals produced by AER and ZPA, respectively.

A self-regulatory system of interlinked signaling feedback loops controls mouse limb patterning.

Embryogenesis depends on self-regulatory interactions between spatially separated signaling centers, but few of these are well understood. Limb development is regulated by epithelial-mesenchymal (e-m) feedback loops between sonic hedgehog (SHH) and fibroblast growth factor (FGF) signaling involving the bone morphogenetic protein (BMP) antagonist Gremlin1 (GREM1). By combining mouse molecular genetics with mathematical modeling, we showed that BMP4 first initiates and SHH then propagates e-m feedback signaling through differential transcriptional regulation of Grem1 to control digit specification.

Delayed closed reduction of rotatory atlantoaxial dislocation in an adult.

We report a case of rotatory atlantoaxial dislocation due to a rugby injury in an adult. The patient presented with torticollis 4 weeks after the injury. The neurological evaluation was normal.

[Comminuted fractures in multiple trauma patients: an analysis of 31 cases].

Purpose Of The Study: We analyzed calcaneum burst fractures in multiple trauma patients and propose a management scheme.

Material And Methods: In a retrospective study, we isolated 23 patients with 31 calcaneum burst fractures. All were stage V in the Duparc classification.

[Direct cost assessment of wrist fractures].

Purpose Of The Study: The cost effectiveness of wrist fractures in 1996 at Pitié-Salpétrière Hospital in Paris has been thoroughly analysed. The purpose of this retrospective study was to identify the factors responsible for the variation in the treatment cost of those fractures.

Material And Methods: Cost, hospital stay, functional status, ASA score and surgical treatment were analysed in 53 patients with a median age of 57 years.

[Ipsilateral hip and femoral shaft fractures: components of therapeutic choice].

Purpose Of Study: Ten cases of ipsilateral hip and femoral shaft fractures were reviewed.

Material And Methods: All patients were treated operatively for both fractures between 1988 and 1997 in Pitié Hospital. Five were treated with antegrade reamed intramedullary nails and cancellous screw fixation of the femoral neck, and 5 by long Gamma nail.

HLA DRB1, DMA, and DMB gene polymorphisms in rheumatoid arthritis.

Objective: To study the influence of DMA and DMB genes on susceptibility to Rheumatoid Arthritis (RA).

Methods: HLA-DRB1, DMA and DMB polymorphisms were defined by PCR SSOP in 203 European Mediterranean RA patients and 181 unrelated healthy controls.

Results: No significant difference in the phenotype frequencies of DMA and DMB alleles was observed between patients and controls.

Iliopsoas bursopathies. A review of twelve cases.

Synovial cysts are far less common at the hip than at the knee and usually occur in patients whose hip cavity communicates with the iliopsoas bursa. We report 12 cases of enlargement of the iliopsoas bursa, nine men and three women, with a mean age of 48 years. The six patients with septic bursitis had severe symptoms similar to those seen in septic arthritis of the hip.

[Possibilities of anterior approach to the lumbar spine by minimal retroperitoneal access. Anatomical bases. Technical principles and initial results].

Anterolateral approach to the lumbar spine using a retroperitoneal approach is a common technique. But conventional approaches are performed laterally, resulting in parietal muscular damage, which may alter functional results. The authors present their experience about a minimized pararectal retroperitoneal approach from T12 to S1.

Surgery of the deformities in ankylosing spondylitis: our experience of lumbar osteotomies in 31 patients.

Corrective surgery for kyphotic deformities of the spine in ankylosing spondylitis is a major surgery for rare indications. The authors report 31 lumbar osteotomies. The goal is to correct the deformity through a posterior limited approach and to minimise the neurological risks.

[Surgery of the upper cervical spine in rheumatoid arthritis. Indications and results apropos of 28 cases].

Purpose Of The Study: The goal of this study was to precise indications and surgical techniques for stabilisation with or without decompression of the upper cervical spine instability in rheumatoid arthritis.

Material And Methods: 28 patients presenting upper cervical spine disease have been reviewed (mean age 57 years). These patients had been suffering from severe diffuse arthritis during an average of 14.

[Surgical treatment of deformities of the thoracic and lumbar spine by posterior spinal osteotomy].

From 1987 to 1993, we performed spinal osteotomy with posterior closing-wedge using a single-operation technique in 20 patients with kyphosis. Spinal deformity resulted from mal union after spinal injury in 13 patients and from ankylosing spondylarthritis in 7. Mean duration of the procedure was 4 h 15 min (range 2 h 30 min to 7 h) for mal union and 3 hours (2 h 30 to 4 h) for ankylosing spondylarthritis.

[Surgical treatment of symptomatic thoracic disk hernia: anterior or posterolateral approach?].

From 1981 to 1994, 16 patients with 18 thoracic disk hernias due to degenerative disease (n = 13), trauma (n = 4) or Scheuermann's disease (n = 1) received surgical treatment. Most were situated from T6 to T12. There were 10 medial hernias and 8 lateral hernias.

[Destabilization after surgical treatment of narrow lumbar canal: when should arthrodesis be performed?].

Post-operative spine displacement occurs by excessive or aggravated vertebral sliding. Sex and age, anatomics factors (pre-operative displacement, intersomatic discs quality, hyperlordosis) and operative factors (extensive laminectomy, artherectomy) are predisposing factors. The risk of post-operative vertebral displacement is calculated by a fine pre and per-operative analysis of these pre-disposing factors: Tolerance to post-operative spinal displacement cannot be foreseen and surgical recovery may be difficult whenever.

HLA-DRB1 alleles associated with rheumatoid arthritis in southern France. Absence of extraarticular disease despite expression of the shared epitope.

Objective: Extraarticular rheumatoid arthritis (RA) is almost unknown in Marseille in southern France. We investigated whether this was due to rare expression of the HLA-DRB1 shared epitope.

Methods: HLA-DRB1 alleles were characterized in 73 patients with RA and 108 controls by polymerase chain reaction amplification and oligonucleotide hybridization.

[Neurologic complications of surgery of the spine in adults].

Spine surgery exposes to neurological complications. There were 170 immediate complications of spine surgery at Pitiè-Salpétrière Hospital out of 2,855 reviewed (5.95%) during 9 years.