Disease relevance of Sim2

• The effects of Sim2s on transcriptional regulation through hypoxia, dioxin, and central midline response elements are different than that of full-length Sim2 [1].
• Mice trisomic for a bacterial artificial chromosome with the single-minded 2 gene (Sim2) show phenotypes similar to some of those present in the partial trisomy 16 mouse models of Down syndrome [2].
• However, Sim2 mutant mice die within 3 days of birth due to lung atelectasis and breathing failure [3].
• Sim2 mutants also develop congenital scoliosis, reflected by the unequal sizes of the left and right vertebrae and ribs [3].
• Craniofacial abnormalities resulting from targeted disruption of the murine Sim2 gene [4].

Psychiatry related information on Sim2

• The single-minded 2 gene (Sim2) plays a crucial role in the mental retardation of Down Syndrome (DS) [5].

High impact information on Sim2

• Sim2 mutants have developmental defects not overlapping with those of Sim1 mutants [3].
• The mouse genome contains two Sim genes, Sim1 and Sim2 [3].
• In the mammalian CNS, Sim2 and Sim1 are coexpressed in the paraventricular nucleus (PVN) [3].
• In order to validate this hypothesis in vivo, we have created the first bacterial artificial chromosome transgenic mice overexpressing a gene possibly involved in DS with only one or two additional copies of mouse Sim2 [2].
• Although Shh expression is maintained in Sim2(-)(/)(-) embryos, it was determined to be absent from the rostral midbrain and caudal diencephalon of embryos carrying a dominant-negative transgene that disrupts the function of bHLH-PAS proteins [6].

Biological context of Sim2

• Sim2 contributes to neuroendocrine hormone gene expression in the anterior hypothalamus [7].
• We show here that the activity of one Shh enhancer, which directs reporter expression to portions of the ventral midbrain and diencephalon, overlaps both temporally and spatially with the expression of Sim2 [6].
• The developing palates of the Sim2 -/- mice are hypocellular, and at embryonic day 14.5 contain excess extracellular matrix component hyaluronan (HA) compared with heterozygotes and homozygous wild-type littermates [4].
• Effect of mouse Sim2 gene on the cell cycle of PC12 cells [8].

Anatomical context of Sim2

• Sim2s is expressed at high levels in kidney and skeletal muscle; however, the ratio of Sim2 to Sim2s mRNA differs between these tissues [1].
• Mice homozygous for the disrupted allele (Sim2 -/-) exhibit a cleft of the secondary palate and malformations of the tongue and pterygoid processes of the sphenoid bone [4].
• These craniofacial malformations are the most probable cause of aerophagia (air swallowing with subsequent accumulation of air in the gastrointestinal tract) and postnatal death exhibited by Sim2 -/- mice [4].
• Sim2 is a member of the basic helix-loop-helix PAS transcription factor gene family and is evolutionarily related to the Drosophila single-minded gene, a key regulator of central nervous system midline development [4].
• To explore how Sim2 influences spatial memory, a DNA plasmid-encoding mouse Sim2 (mSim2) wrapped with liposome was bilaterally injected into the hippocampus of rats [5].

Associations of Sim2 with chemical compounds

• Specifically, Sim2s exerts a less repressive effect on hypoxia-induced gene expression than full-length Sim2, but is just as effective as Sim2 at repressing TCDD-induced gene expression from a dioxin response element [1].
• Sim2 encodes a basic helix-loop-helix (bHLH-PAS) PAS domain containing transcriptional regulator whose Drosophila homolog, single-minded, is a master regulator of ventral midline development [6].

Other interactions of Sim2

• Genetically, Sim1 acts upstream of Sim2 and partially compensates for the loss of Sim2 [7].
• Similar to full-length Sim2, Sim2s interacts with Arnt and to a lesser extent, Arnt2 [1].
• 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 [7].
• In addition, alterations in the Sim-2 expression domain in ventral prosencephalon, rostral to p1, provide novel evidence for Wnt-1 function in this region [9].
• It is concluded that Sim2 may play an important role in the pathogenesis of DS by inhibiting the cell cycle, which is related to the decreased expression of cyclin E and increased expression of p27 [8].

Analytical, diagnostic and therapeutic context of Sim2

• In an effort to determine the biological roles of Sim2 in mammalian development, we disrupted the murine Sim2 gene through gene targeting [4].

References