Severe pancreas hypoplasia and multicystic renal dysplasia in two human fetuses carrying novel HNF1beta/MODY5 mutations.

Heterozygous mutations in the HNF1beta/vHNF1/TCF2 gene cause maturity-onset diabetes of the young (MODY5), associated with severe renal disease and abnormal genital tract. Here, we characterize two fetuses, a 27-week male and a 31.5-week female, carrying novel mutations in exons 2 and 7 of HNF1beta, respectively.

RBP-Jkappa-dependent notch signaling is dispensable for mouse early embryonic development.

The Notch signaling pathway is an evolutionarily conserved signaling system which has been shown to be essential in cell fate specification and in numerous aspects of embryonic development in all metazoans thus far studied. We recently demonstrated that several components of the Notch signaling pathway, including the four Notch receptors and their five ligands known in mammals, are expressed in mouse oocytes, in mouse preimplantation embryos, or both. This suggested a possible implication of the Notch pathway in the first cell fate specification of the dividing mouse embryo, which results in the formation of the blastocyst.

Nas transgenic mouse line allows visualization of Notch pathway activity in vivo.

The Notch signaling pathway plays multiple and important roles in mammals. However, several aspects of its action, in particular, the precise mapping of its sites of activity, remain unclear. To address this issue, we generated a transgenic line carrying a construct consisting of a nls-lacZ reporter gene under the control of a minimal promoter and multiple RBP-Jkappa binding sites.

The murine ortholog of notchless, a direct regulator of the notch pathway in Drosophila melanogaster, is essential for survival of inner cell mass cells.

Notch signaling is an evolutionarily conserved pathway involved in intercellular communication and is essential for proper cell fate choices. Numerous genes participate in the modulation of the Notch signaling pathway activity. Among them, Notchless (Nle) is a direct regulator of the Notch activity identified in Drosophila melanogaster.

Defective chondrocyte proliferation and differentiation in osteochondromas of MHE patients.

Multiple hereditary exostoses (MHE) is an autosomal dominant skeletal disorder caused by mutations in one of the two EXT genes and characterized by multiple osteochondromas that generally arise near the ends of growing long bones. Defective endochondral ossification is likely to be involved in the formation of osteochondromas. In order to investigate potential changes in chondrocyte proliferation and/or differentiation during this process, osteochondroma samples from MHE patients were obtained and used for genetic, morphological, immunohistological, and in situ hybridization studies.

Expression of fibroblast growth factors 18 and 23 during human embryonic and fetal development.

Fibroblast Growth Factor (FGF) 18 and 23 are two recently identified members of the FGF family, a family of structurally related polypeptides with diverse roles in physiological and pathological processes. Studies mostly performed in rodents and chicken have demonstrated that FGF18 is a pleiotropic growth factor involved in the development of various organs, while there are no data supporting a direct role of FGF23 in cell proliferation or differentiation either in physiology or pathology in any species. However, it is now established that FGF23 can be a humoral messenger and an important regulator of phosphate homeostasis and vitamin D metabolism.

Developmental expression of the Notch signaling pathway genes during mouse preimplantation development.

Notch signaling is an evolutionary conserved pathway involved in intercellular signaling and essential for proper cell fate choices during development. Thus, it could be involved in mouse preimplantation development where intercellular signaling plays a crucial role, particularly between the inner cell mass and the trophectoderm of the blastocyst. At their face value, the phenotypes observed when disrupting each of the four Notch genes known in the mouse do not support this view as none of them involves perturbation of preimplantation development.

Expression patterns of parathyroid hormone-related peptide (PTHrP) and parathyroid hormone receptor type 1 (PTHR1) during human development are suggestive of roles specific for each gene that are not mediated through the PTHrP/PTHR1 paracrine signaling pathway.

Close temporal and spatial relationships between Pthrp and Pthr1 gene expression are reported during fetal life in rats, suggestive of a developmental role via a paracrine signaling pathway. In agreement, disruption of this signaling pathway is associated with developmental defects, as documented in mice and humans. Surprisingly, however, only few organs are affected.

Parathyroid hormone receptor type 1/Indian hedgehog expression is preserved in the growth plate of human fetuses affected with fibroblast growth factor receptor type 3 activating mutations.

The fibroblast growth factor receptor type 3 (FGFR3) and Indian hedgehog (IHH)/parathyroid hormone (PTH)/PTH-related peptide receptor type 1 (PTHR1) systems are both essential regulators of endochondral ossification. Based on mouse models, activation of the FGFR3 system is suggested to regulate the IHH/PTHR1 pathway. To challenge this possible interaction in humans, we analyzed the femoral growth plates from fetuses carrying activating FGFR3 mutations (9 achondroplasia, 21 and 8 thanatophoric dysplasia types 1 and 2, respectively) and 14 age-matched controls by histological techniques and in situ hybridization using riboprobes for human IHH, PTHR1, type 10 and type 1 collagen transcripts.