Biomedical subjects

Isabelle Bar

Publications and source records attributed to Isabelle Bar.

4 recordsLinked to original sources

PubMed2005

Protocadherin Celsr3 is crucial in axonal tract development.

In the embryonic CNS, the development of axonal tracts is required for the formation of connections and is regulated by multiple genetic and microenvironmental factors. Here we show that mice with inactivation of Celsr3, an ortholog of Drosophila melanogaster flamingo (fmi; also known as starry night, stan) that encodes a seven-pass protocadherin, have marked, selective anomalies of several major axonal fascicles, implicating protocadherins in axonal development in the mammalian CNS for the first time. In flies, fmi controls planar cell polarity (PCP) in a frizzled-dependent but wingless-independent manner. The neural phenotype in Celsr3 mutant mice is similar to that caused by inactivation of Fzd3, a member of the frizzled family. Celsr3 and Fzd3 are expressed together during brain development and may act in synergy. Thus, a genetic pathway analogous to the one that controls PCP is key in the development of the axonal blueprint.

Animals↗

PubMed2004

SOX9 is up-regulated by the transient expression of SRY specifically in Sertoli cell precursors.

The Y chromosome gene Sry encodes a transcription factor required to initiate testis development. The related autosomal gene Sox9 is up-regulated shortly after the onset of Sry transcription and is thought essential for the differentiation of Sertoli cells. The lineage that gives rise to Sertoli cells has its origins within the coelomic epithelium (CE) of the genital ridge, but from cells also able to give rise to an interstitial cell type. It was not known at what point SRY acts in the derivation of this lineage or how the two genes interact. To investigate the identity of the cells expressing Sry, we designed two transgenes driven by the Sry promoter: one gives expression of a stable reporter, human placental alkaline phosphatase (hPLAP), while the second gives expression of a functional Myc-epitope tagged SRY protein (SRYMYC). Taking advantage of lasting hPLAP activity after transcription of the reporter gene has ceased, we could show that SryhPLAP was expressed exclusively in all cells fated to become Sertoli cells. SRYMYC-single-positive cells were first observed in the gonad and not in the CE. Subsequently, they became SRYMYC/SOX9-double-positive, but only for a few hours before turning into SOX9-single-positive cells. After the coelomic epithelial cells migrate into the gonad, there is first a decision to become interstitial or supporting cells, and then the transient expression of SRY in the latter determines their fate as Sertoli cells by up-regulating Sox9.

Alkaline Phosphatase↗

PubMed2003

The reelin signaling pathway: some recent developments.

The Reelin signaling pathway plays a key role in the architectonic development of the central nervous system. Extracellular Reelin binds to receptors of the lipoprotein receptor family and induces tyrosine phosphorylation of the adaptor Dab1. In this paper, we discuss three recent developments. First, we show that the central part of Reelin is involved in receptor binding and signal activation as reflected in Dab1 phosphorylation. Second, we examine the genomic organization, alternative splicing and promoter use of the Dab1 gene, which hint at a particularly complex regulation. Third, we present preliminary studies by in situ hybridization that demonstrate regulated expression of Reelin receptors and Dab1 by radial precursors in the ventricular zone.

Cell Adhesion Molecules, Neuronal↗

PubMed2002

The gene encoding disabled-1 (DAB1), the intracellular adaptor of the Reelin pathway, reveals unusual complexity in human and mouse.

The Disabled-1 (Dab1) gene encodes a key regulator of Reelin signaling. Reelin is a large glycoprotein secreted by neurons of the developing brain, particularly Cajal-Retzius cells. The DAB1 protein docks to the intracellular part of the Reelin very low density lipoprotein receptor and apoE receptor type 2 and becomes tyrosine-phosphorylated following binding of Reelin to cortical neurons. In mice, mutations of Dab1 and Reelin generate identical phenotypes. In humans, Reelin mutations are associated with brain malformations and mental retardation; mutations in DAB1 have not been identified. Here, we define the organization of Dab1, which is similar in human and mouse. The Dab1 gene spreads over 1100 kb of genomic DNA and is composed of 14 exons encoding the major protein form, some alternative internal exons, and multiple 5'-exons. Alternative polyadenylation and splicing events generate DAB1 isoforms. Several 5'-untranslated regions (UTRs) correspond to different promoters. Two 5'-UTRs (1A and 1B) are predominantly used in the developing brain. 5'-UTR 1B is composed of 10 small exons spread over 800 kb. With a genomic length of 1.1 Mbp for a coding region of 5.5 kb, Dab1 provides a rare example of genomic complexity, which will impede the identification of human mutations.

Adaptor Proteins, Signal Transducing↗