<b><i>Single-minded</i>—Two Genes,  Three Chromosomes</b>
: Figure 1.

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.

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“…Sim1 is essential for the development of the PVN and SON (24). Sim1 Ϫ/Ϫ mice die perinatally, presumably due to the lack of PVN and SON.…”

Section: Sim2 Mutant Displays No Additive Phenotype In the Sim1mentioning

confidence: 99%

Sim2 Mutants Have Developmental Defects Not Overlapping with Those of Sim1 Mutants

Goshu

Jin

Fasnacht

et al. 2002

Molecular and Cellular Biology

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“…Two mammalian sim orthologs (Sim1 and Sim2) have been discovered that share a number of functional similarities with Drosophila sim (for review, see Michaud and Fan 1997). Both Sim1 and Sim2 proteins dimerize with mammalian Arnt and bind the CME in vitro (Ema et al 1997a;Probst et al 1997).…”

Section: Mammalian Sim and Down Syndromementioning

confidence: 99%

“…The Sim genes are expressed early in brain development suggesting that they might play roles in neurogenesis analogous to Drosophila sim. The roles of Sim1 and Sim2 in embryonic development should be soon forthcoming since both genes have been knocked out in mice (Michaud and Fan 1997). One other distinction is that cell culture transfection experiments suggest that both mammalian Sim proteins function as transcriptional repressors (Ema et al 1997a;Moffett et al 1997).…”

Section: Mammalian Sim and Down Syndromementioning

confidence: 99%

Control of cell lineage-specific development and transcription by bHLH-PAS proteins

Crews¹

1998

Genes & Development

311

229

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“…SIM2 can heterodimerize with aryl hydrocarbon receptor nuclear translocator (ARNT) and translocate to the nucleus to transcriptionally regulate gene expression [3]. Expression of SIM2 mRNA has been detected in fetal brain regions associated with DS pathology [4].…”

Section: Introductionmentioning

confidence: 99%

Potential contribution of SIM2 and ETS2 functional polymorphisms in Down syndrome associated malignancies

et al. 2013

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BackgroundProper expression and functioning of transcription factors (TFs) are essential for regulation of different traits and thus could be crucial for the development of complex diseases. Subjects with Down syndrome (DS) have a higher incidence of acute lymphoblastic leukemia (ALL) while solid tumors, like breast cancer (BC) and oral cancer (OC), show rare incidences. Triplication of the human chromosome 21 in DS is associated with altered genetic dosage of different TFs. V-ets erythroblastosis virus E26 oncogene homolog 2 (ETS2) and Single Minded 2 (SIM2) are two such TFs that regulate several downstream genes involved in developmental and neurological pathways. Here we studied functional genetic polymorphisms (fSNP) in ETS2 and SIM2 encoding genes in a group of patients and control subjects to better understand association of these variants with DS phenotypes.MethodsWe employed an in silico approach to identify potential target pathways of ETS2 and SIM2. fSNPs in genes encoding for these two TFs were identified using available databases. Selected sites were genotyped in individuals with DS, their parents, ALL, BC, OC as well as ethnically matched control individuals. We further analyzed these data by population-based statistical methods.ResultsAllelic/genotypic association analysis showed significant (P < 0.03) differences of rs2070530, rs1051476, rs11254, rs711 for DS subjects compared to control. rs711 also exhibited significantly different genotypic distribution pattern in parents of DS probands (P < 0.02) and BC patients (P < 0.02). Interaction analysis revealed independent main effect of rs711 in all the groups, while rs11254 exhibited independent main effect in DS subjects only. High entropy values were noticed for rs461155 in the solid tumor groups. Significant interactive effects of rs2070531 with rs1051475, rs1051476, rs11254 were observed in all the groups except DS.ConclusionsWe infer from the present investigation that the difference in frequencies of fSNPs and their independent as well as interactive effects may be the cause for altered expression of SIM2 and ETS2 in DS and malignant groups, which affects different downstream biological pathways. Thus, altered expression of SIM2 and ETS2 could be one of the reasons for variable occurrence of different malignant conditions in DS.

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Single-minded—Two Genes, Three Chromosomes : Figure 1.

Cited by 13 publications

References 36 publications

Sim2 Mutants Have Developmental Defects Not Overlapping with Those of Sim1 Mutants

Sim2 Mutants Have Developmental Defects Not Overlapping with Those of Sim1 Mutants

Control of cell lineage-specific development and transcription by bHLH-PAS proteins

Potential contribution of SIM2 and ETS2 functional polymorphisms in Down syndrome associated malignancies

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