Biomedical subjects

Jacques L Michaud

Publications and source records attributed to Jacques L Michaud.

14 recordsLinked to original sources

PubMed2026

De novo variants in the poly(rC)-binding protein gene PCBP1 cause a neurodevelopmental disorder.

Poly(rC)-binding protein 1 (PCBP1), a splicing factor and key member of the hnRNP E family, was initially characterized for its tumor suppressive properties. More recently, its role in gene regulation in the brain and nervous system has attracted growing interest. Through an international multicenter collaboration, we identified 16 de novo pathogenic variants in PCBP1 across 17 subjects from 16 unrelated families. All affected individuals exhibited intellectual disability (ID), with autism spectrum disorder (ASD) as a prominent feature. Functional analysis in primary hippocampal mouse neuron cultures indicated that PCBP1 variants impair dendritic arborization, underscoring their deleterious effects. Transcriptomic profiling by RNA sequencing of subject-derived T cells showed a distinctive signature characterized by significantly increased exon skipping. These results highlight the contribution of PCBP1 in neurogenesis and neuritogenesis, which is impacted by loss-of-function variants expressed in neuronal cells, thereby supporting the link between splicing defects and neurodevelopmental disorders. Collectively, our findings demonstrate the prominent role of PCBP1 in neurodevelopment, reaffirming the importance of splicing regulation in mammalian neurodevelopment.

Journal Article↗

PubMed2006

Recurrent pancreatitis in mitochondrial cytopathy.

Diabetes mellitus and exocrine insufficiency are the commonest pancreatic manifestations of mitochondrial diseases. In contrast, pancreatitis has rarely been described in mitochondrial syndromes. We report on a patient with Kearns-Sayre syndrome and recurrent episodes of acute pancreatitis for which no explanation could be found other than the associated mitochondrial dysfunction. Interestingly, pharmacological disruption of mitochondrial metabolism in various models as well as in patients can cause pancreatitis, further supporting this association. A diagnosis of pancreatitis should be considered in any patients with mitochondrial disease and recurrent abdominal pain.

Acute Disease↗

PubMed2006

Mutations in the gene encoding the 3'-5' DNA exonuclease TREX1 cause Aicardi-Goutières syndrome at the AGS1 locus.

Aicardi-Goutières syndrome (AGS) presents as a severe neurological brain disease and is a genetic mimic of the sequelae of transplacentally acquired viral infection. Evidence exists for a perturbation of innate immunity as a primary pathogenic event in the disease phenotype. Here, we show that TREX1, encoding the major mammalian 3' --> 5' DNA exonuclease, is the AGS1 gene, and AGS-causing mutations result in abrogation of TREX1 enzyme activity. Similar loss of function in the Trex1(-/-) mouse leads to an inflammatory phenotype. Our findings suggest an unanticipated role for TREX1 in processing or clearing anomalous DNA structures, failure of which results in the triggering of an abnormal innate immune response.

Animals↗

PubMed2006

Adenoviral-mediated modulation of Sim1 expression in the paraventricular nucleus affects food intake.

Haploinsufficency of Sim1, which codes for a basic helix-loop-helix-PAS (PER-ARNT-SIM) transcription factor, causes hyperphagia in mice and humans, without decrease in energy expenditure. Sim1 is expressed in several areas of the brain, including the developing and postnatal paraventricular nucleus (PVN), a region of the hypothalamus that controls food intake. We have previously found that the number of PVN cells is decreased in Sim1+/- mice, suggesting that their hyperphagia is caused by a developmental mechanism. However, the possibility that Sim1 functions in the postnatal PVN to control food intake cannot be ruled out. To explore this hypothesis, we used adenoviral vectors to modulate Sim1 expression in the postnatal PVN of wild-type mice. Unilateral stereotaxic injection into the PVN of an adenoviral vector producing a short hairpin RNA directed against Sim1 resulted in a significant increase in food intake, which peaked to 22% 6 d after the procedure, compared with the injection of a control virus. In contrast, injection of an adenovirus that expresses Sim1 induced a decrease in food intake that was maximal on the seventh day after the procedure, reaching 20%. The impact of bilateral injections of these vectors into the PVN was not greater than that of unilateral injections. Together, these results strongly suggest that Sim1 functions along a physiological pathway to control food intake.

Adenoviridae↗

PubMed2006

Laminar organization of the early developing anterior hypothalamus.

The bHLH-PAS transcription factor SIM1 is required for the development of neurons of the anterior hypothalamus (AH). In order to dissect this developmental program, we compared gene expression in the AH of E12.5 Sim1(+/+) and Sim1(-/-) littermates using an oligonucleotide-based microarray. Our analysis identified 48 genes that were downregulated and 8 genes that were upregulated. We examined the expression pattern of 10 of the identified genes--Cart, Cbln1, Alcam, Unc-13c, Rgs4, Lnx4, Irx3, Sax1, Ldb2 and Neurod6--by in situ hybridization in E12.5 embryos. All of these genes are expressed in domains that are contained within that of Sim1 and their expression is changed in Sim1(-/-) embryos as predicted by the microarray analysis. Classical dating studies have established that the hypothalamus follows an "outside-in" pattern of neurogenesis, with neurons of the lateral hypothalamus being born before the medial ones. Analysis of the genes identified in this microarray study showed that the developing AH is characterized by different layers of gene expression that most likely correspond to distinct waves of neurogenesis. In addition, our analysis suggests that Sim1 function is required for the production or the survival of postmitotic neurons as well as for correct positioning of AH neurons.

Animals↗

PubMed2005

Sim1 and Sim2 are required for the correct targeting of mammillary body axons.

The mammillary body (MB), and its axonal projections to the thalamus (mammillothalamic tract, MTT) and the tegmentum (mammillotegmental tract, MTEG), are components of a circuit involved in spatial learning. The bHLH-PAS transcription factors SIM1 and SIM2 are co-expressed in the developing MB. We have found that MB neurons are generated and that they survive at least until E18.5 in embryos lacking both Sim1 and Sim2 (Sim1(-/-);Sim2(-/-)). However, the MTT and MTEG are histologically absent in Sim1(-/-);Sim2(-/-) embryos, and are reduced in embryos lacking Sim1 but bearing one or two copies of Sim2, indicating a contribution of the latter to the development of MB axons. We have generated, by homologous recombination, a null allele of Sim1 (Sim1(tlz)) in which the tau-lacZ fusion gene was introduced, allowing the staining of MB axons. Consistent with the histological studies, lacZ staining showed that the MTT/MTEG is barely detectable in Sim1(tlz/tlz);Sim2(+/-) and Sim1(tlz/tlz);Sim2(-/-) brains. Instead, MB axons are splayed and grow towards the midline. Slit1 and Slit2, which code for secreted molecules that induce the repulsion of ROBO1-producing axons, are expressed in the midline at the level of the MB, whereas Robo1 is expressed in the developing MB. The expression of Rig-1/Robo3, a negative regulator of Slit signalling, is upregulated in the prospective MB of Sim1/Sim2 double mutants, raising the possibility that the growth of mutant MB axons towards the midline is caused by a decreased sensitivity to SLIT. Finally, we found that Sim1 and Sim2 act along compensatory, but not hierarchical, pathways, suggesting that they play similar roles in vivo.

Animals↗

PubMed2005

Looking for trouble: a search for developmental defects of the hypothalamus.

The hypothalamus is a critical integrator of several homeostatic processes that are required for the survival of vertebrates. Disruption of the development of the hypothalamus thus has the potential of perturbing important physiological processes with lifelong consequences. We review current knowledge about how cell types are specified and circuits are formed within the developing hypothalamus. We emphasize the potential clinical impact of the perturbations of these pathways using the regulation of energy balance as a model. We predict that disruption of hypothalamic development is a common, previously unsuspected cause of disorders of homeostatic processes such as obesity and high blood pressure.

Animals↗

PubMed2005

Regionalization of the anterior hypothalamus in the chick embryo.

Loss-of-function experiments in mice have shown that the transcription factors Sim1, Otp, Sim2, and Brn2 form a cascade essential for the differentiation of neuroendocrine cells of the anterior hypothalamus that produce vasopressin, oxytocin, somatostatin (SS), thyrotropin-releasing hormone (TRH), and corticotropin-releasing hormone (CRH). Very little is known about how the differentiation of these cell types is regulated in chick. Here, we report the cloning of the chick homolog of Otp. Moreover, we have systematically compared the expression of Sim1, Sim2, Brn2, and Otp with that of the markers of terminal differentiation TRH, SS, CRH, vasotocin, and mesotocin during development of chick embryos. We have found that the cell types studied generally develop in domains expressing these transcriptional regulators but that the pattern of neuronal differentiation and the spatial distribution of some regulators were not the same as in mice. Our results provide a framework useful for the functional analysis of hypothalamus development in chick.

Animals↗

PubMed2004

G protein-coupled receptor-dependent development of human frontal cortex.

The mammalian cerebral cortex is characterized by complex patterns of anatomical and functional areas that differ markedly between species, but the molecular basis for this functional subdivision is largely unknown. Here, we show that mutations in GPR56, which encodes an orphan G protein-coupled receptor (GPCR) with a large extracellular domain, cause a human brain cortical malformation called bilateral frontoparietal polymicrogyria (BFPP). BFPP is characterized by disorganized cortical lamination that is most severe in frontal cortex. Our data suggest that GPCR signaling plays an essential role in regional development of human cerebral cortex.

Amino Acid Substitution↗

PubMed2004

Sim2 contributes to neuroendocrine hormone gene expression in the anterior hypothalamus.

Paraventricular (PVN) and supraoptic nuclei of the hypothalamus maintain homeostasis by modulating pituitary hormonal output. PVN and supraoptic nuclei contain five major cell types: oxytocin-, vasopressin-, CRH-, somatostatin-, and TRH-secreting neurons. Sim1, Arnt2, and Otp genes are essential for terminal differentiation of these neurons. One of their common downstream genes, Brn2, is necessary for oxytocin, vasopressin, and CRH cell differentiation. Here we show that Sim2, a paralog of Sim1, contributes to the expression of Trh and Ss genes in the dorsal preoptic area, anterior-periventricular nucleus, and PVN. Sim2 expression overlaps with Trh- and Ss-expressing cells, and Sim2 mutants contain reduced numbers of Trh and Ss cells. Genetically, Sim1 acts upstream of Sim2 and partially compensates for the loss of Sim2. Comparative expression studies at the anterior hypothalamus at early stages reveal that there are separate pools of Trh cells with distinctive molecular codes defined by Sim1 and Sim2 expression. Together with previous reports, our results demonstrate that Sim1 and Otp utilize two common downstream genes, Brn2 and Sim2, to mediate distinctive sets of neuroendocrine hormone gene expression.

Animals↗

PubMed2004

Wolcott-Rallison Syndrome: clinical, genetic, and functional study of EIF2AK3 mutations and suggestion of genetic heterogeneity.

Wolcott-Rallison syndrome (WRS) is a rare autosomal-recessive disorder characterized by the association of permanent neonatal or early-infancy insulin-dependent diabetes, multiple epiphyseal dysplasia and growth retardation, and other variable multisystemic clinical manifestations. Based on genetic studies of two inbred families, we previously identified the gene responsible for this disorder as EIF2AK3, the pancreatic eukaryotic initiation factor 2alpha (eIF2alpha) kinase. Here, we have studied 12 families with WRS, totalling 18 cases. With the exception of one case, all patients carried EIF2AK3 mutations resulting in truncated or missense versions of the protein. Exclusion of EIF2AK3 mutations in the one patient case was confirmed by both linkage and sequence data. The activities of missense versions of EIF2AK3 were characterized in vivo and in vitro and found to have a complete lack of activity in four mutant proteins and residual kinase activity in one. Remarkably, the onset of diabetes was relatively late (30 months) in the patient expressing the partially defective EIF2AK3 mutant and in the patient with no EIF2AK3 involvement (18 months) compared with other patients (<6 months). The patient with no EIF2AK3 involvement did not have any of the other variable clinical manifestations associated with WRS, which supports the idea that the genetic heterogeneity between this variant form of WRS and EIF2AK3 WRS correlates with some clinical heterogeneity.

Adolescent↗

PubMed2003

Regulatory interaction between arylhydrocarbon receptor and SIM1, two basic helix-loop-helix PAS proteins involved in the control of food intake.

The basic helix-loop-helix PAS (bHLH-PAS) transcription factors SIM1 and arylhydrocarbon receptor (AHR) are involved in the control of feeding behavior. Sim1 haploinsufficiency causes hyperphagia in mice and humans, most likely by perturbing the hypothalamus function. The administration of 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD), a ligand of AHR, causes severe anorexia, which also appears to be of central origin. Both SIM1 and AHR require heterodimerization either with ARNT or ARNT2 to function. Here, we characterize the promoter for Sim1 and show that a consensus AHR-ARNT/2 binding site positively regulates its activity in the context of transfection experiments in Neuro-2A cells. A gel shift assay indicated that AHR-ARNT/2 can bind its putative site in the Sim1 promoter. Overexpression of Arnt, Arnt2, or Ahr increased the activity of a reporter construct containing the Sim1 promoter by 1.8-, 1.5-, and 2.2-fold, respectively, but failed to do so when the AHR-ARNT/2 binding site was mutated. Similarly, TCDD increased the activity of the reporter construct by 1.8-fold but not that of its mutated version. Finally, we found that TCDD increased Sim1 expression in Neuro-2A cells and in mouse kidney and hypothalamus by 4-, 3-, and 2-fold, respectively. We conclude that Sim1 expression is regulated by AHR-ARNT/2. This result raises the possibility that Sim1 mediates the effect of TCDD on feeding and points to a complex network of regulatory interactions between bHLH-PAS proteins.

Animals↗

PubMed2002

Sim2 mutants have developmental defects not overlapping with those of Sim1 mutants.

The mouse genome contains two Sim genes, Sim1 and Sim2. They are presumed to be important for central nervous system (CNS) development because they are homologous to the Drosophila single-minded (sim) gene, mutations in which cause a complete loss of CNS midline cells. In the mammalian CNS, Sim2 and Sim1 are coexpressed in the paraventricular nucleus (PVN). While Sim1 is essential for the development of the PVN (J. L. Michaud, T. Rosenquist, N. R. May, and C.-M. Fan, Genes Dev. 12:3264-3275, 1998), we report here that Sim2 mutant has a normal PVN. Analyses of the Sim1 and Sim2 compound mutants did not reveal obvious genetic interaction between them in PVN histogenesis. However, Sim2 mutant mice die within 3 days of birth due to lung atelectasis and breathing failure. We attribute the diminished efficacy of lung inflation to the compromised structural components surrounding the pleural cavity, which include rib protrusions, abnormal intercostal muscle attachments, diaphragm hypoplasia, and pleural mesothelium tearing. Although each of these structures is minimally affected, we propose that their combined effects lead to the mechanical failure of lung inflation and death. Sim2 mutants also develop congenital scoliosis, reflected by the unequal sizes of the left and right vertebrae and ribs. The temporal and spatial expression patterns of Sim2 in these skeletal elements suggest that Sim2 regulates their growth and/or integrity.

Animals↗

PubMedDate not supplied

Obstetric US: watch the fetal hands.

Hand anomalies are difficult to diagnose and are often overlooked during prenatal ultrasonography (US). The spectrum of malformations varies from subtle finger deformities to the complete amputation of limbs. Malformations of the hand can be classified, according to the predominant anomaly, among the following categories: alignment abnormalities (clenched hand, camptodactyly, clinodactyly, hypokinesia, clubhand, phocomelia), thumb anomalies, abnormal size (macrodactyly, trident hand), abnormal echogenicity (abnormal calcifications), abnormal number (polydactyly, syndactyly, ectrodactyly), and constriction band sequence. A fetal hand anomaly has important diagnostic and prognostic implications as well as functional consequences. Malformation may be isolated but often is associated with a syndrome or karyotype anomaly. Classification and characterization of the anomaly help to narrow the differential diagnosis: Some malformations (clenched hand, hitchhiker thumb) are highly suggestive of a specific diagnosis. The detection of a fetal hand malformation warrants a complete work-up, including complete fetal and cardiac US examinations, as well as genetic counseling to determine whether familial inquiry and karyotype analysis are necessary.

Hand Deformities, Congenital↗