Autosomal recessive renal tubular dysgenesis (RTD) is a severe disorder of renal tubular development characterized by early onset and persistent fetal anuria leading to oligohydramnios and the Potter sequence, associated with skull ossification defects. Early death occurs in most cases from anuria, pulmonary hypoplasia, and refractory arterial hypotension. The disease is linked to mutations in the genes encoding several components of the renin-angiotensin system (RAS): AGT (angiotensinogen), REN (renin), ACE (angiotensin-converting enzyme), and AGTR1 (angiotensin II receptor type 1). Here, we review the series of 54 distinct mutations identified in 48 unrelated families. Most of them are novel and ACE mutations are the most frequent, observed in two-thirds of families (64.6%). The severity of the clinical course was similar whatever the mutated gene, which underlines the importance of a functional RAS in the maintenance of blood pressure and renal blood flow during the life of a human fetus. Renal hypoperfusion, whether genetic or secondary to a variety of diseases, precludes the normal development/ differentiation of proximal tubules. The identification of the disease on the basis of precise clinical and histological analyses and the characterization of the genetic defects allow genetic counseling and early prenatal diagnosis.

The early stages of human lymphopoiesis are poorly characterized. Here, we compared the lymphoid potential of a novel umbilical cord blood CD34 ؉ CD45RA hi CD7 ؉ hematopoietic progenitor cell (HPC) population with that of CD34 ؉ CD45RA hi Lin ؊ CD10 ؉ HPCs, previously proposed as candidate common lymphoid progenitors. Limitingdilution and clonal analysis, fetal thymic organ cultures, and culture onto Notch ligand Delta-like-1-expressing OP9 cells, showed that although CD34 ؉ CD45RA hi CD7 ؉ HPCs could generate cells of the 3 lymphoid lineages, their potential was skewed toward the T/natural killer (T/NK) lineages. In contrast, CD34 ؉ CD45RA hi Lin ؊ CD10 ؉ HPCs predominantly exhibited a B-cell potential. Gene expression profiling with DNA microarrays confirmed that CD34 ؉ CD45RA hi CD7 ؉ HPCs selectively expressed T-lymphoid and NK lineage-committed genes while retaining expression of genes affiliated to the granulomonocytic lineage, whereas CD34 ؉ CD45RA hi Lin ؊ CD10 ؉ HPCs displayed a typical pro-B-cell transcription profile and essentially lacked genes unrelated to the B lineage. In addition, both populations could be generated in vitro from CD34 ؉ CD45RA int CD7 ؊ and CD34 ؉ CD45RA hi Lin ؊ HPCs with mixed lymphomyeloid potential, from which they emerged independently with different growth/ differentiation factor requirements. These findings indicate that CD34 ؉ CD45RA hi CD7 ؉ and CD34 ؉ CD45RA hi Lin ؊ CD10 ؉ HPCs correspond to multipotent early lymphoid progenitors polarized toward either the T/NK or B lineage, respectively. IntroductionThe immediate progeny of pluripotent hematopoietic stem cells is thought to correspond to common myeloid progenitors (CMPs) and common lymphoid progenitors (CLPs). CMPs are assumed to give rise to granulocytes and macrophages, as well as to the erythroid and megakaryocytic lineages, whereas CLPs are committed to generate either B lymphocytes (BLs) or T lymphocytes (TLs) and natural killer (NK) cells. 1,2 Evidence for a primary segregation between CLPs and CMPs stems from in vivo transfer experiments in adult mice, where 2 populations of c-Kit lo Sca lo IL-7R ϩ and Fc␥R lo CD34 ϩ hematopoietic progenitor cells (HPCs) isolated from the postnatal bone marrow (BM) were shown to selectively reconstitute either the lymphoid 3 or erythromegakaryocytic and granulomonocytic lineages. 4 Such a dichotomous model of hematopoiesis remains however debated because there is also evidence that multilineage precursors coexpress lymphoid as well as myeloerythroid genes [5][6][7] and that populations of early lymphoid progenitors (ELPs) retain some degree of multipotency. [8][9][10][11] For example, AA4.1 ϩ Fc␥R ϩ fetal precursors with TL and BL potential retain significant macrophage potential but fail to generate erythroid or granulocytic cells. 8 In line with these findings, early GFP lo c-kit hi Sca-1 ϩ BL precursors from RAG1/GFP (recombination activating gene 1/green fluorescent protein) knock-in mice still express TL and macrophage potential when cultured under appropriate conditions...

Spinal muscular atrophy (SMA) is a common autosomal recessive neuromuscular disorder characterized by degeneration of motor neurons of the spinal cord and muscular atrophy. SMA is caused by alterations to the survival of motor neuron (SMN) gene, the function of which has hitherto been unclear. Here, we present immunoblot analyses showing that normal SMN protein expression undergoes a marked decay in the postnatal period compared with fetal development. Morphological and immunohistochemical analyses of the SMN protein in human fetal tissues showed a general distribution in the cytoplasm, except in muscle cells, where SMN protein was immunolocalized to large cytoplasmic dot-like structures and was tightly associated with membrane-free heavy sedimenting complexes. These cytoplasmic structures were similar in size to gem. The SMN protein was markedly deficient in tissues derived from type I SMA fetuses, including skeletal muscles and, as previously shown, spinal cord. While our data do not help decide whether SMA results from impaired SMN expression in spinal cord, skeletal muscle or both, they suggest a requirement for SMN protein during embryo-fetal development.

The molecular mechanisms that lead to the cognitive defects characteristic of Down syndrome (DS), the most frequent cause of mental retardation, have remained elusive. Here we use a transgenic DS mouse model (152F7 line) to show that DYRK1A gene dosage imbalance deregulates chromosomal clusters of genes located near neuron-restrictive silencer factor (REST/NRSF) binding sites. We found that Dyrk1a binds the SWI/SNF complex known to interact with REST/NRSF. The mutation of a REST/NRSF binding site in the promoter of the REST/NRSF target gene L1cam modifies the transcriptional effect of Dyrk1a-dosage imbalance on L1cam. Dyrk1a dosage imbalance perturbs Rest/Nrsf levels with decreased Rest/Nrsf expression in embryonic neurons and increased expression in adult neurons. Using transcriptome analysis of embryonic brain subregions of transgenic 152F7 mouse line, we identified a coordinated deregulation of multiple genes that are responsible for dendritic growth impairment present in DS. Similarly, Dyrk1a overexpression in primary mouse cortical neurons induced severe reduction of the dendritic growth and dendritic complexity. We propose that DYRK1A overexpression-related neuronal gene deregulation via disturbance of REST/NRSF levels, and the REST/NRSF-SWI/SNF chromatin remodelling complex, significantly contributes to the neural phenotypic changes that characterize DS.