Spatial and temporal localization during embryonic and fetal human development of the transcription factor SIM2 in brain regions altered in Down syndrome

Abstract

Human SIM2 is the ortholog of Drosophila single-minded (sim), a master regulator of neurogenesis and transcriptional factor controlling midline cell fate determination. We previously localized SIM2 in a chromosome 21 critical region for Down syndrome (DS). Here, we studied SIM2 gene using a new approach to provide insights in understanding of its potential role in human development. For the first time, we showed SIM2 spatial and temporal expression pattern during human central nervous system (CNS) development, from embryonic to fetal stages. Additional investigations were performed using a new optic microscopy technology to compare signal intensity and cell density [M. Rachidi, C. Lopes, S. Gassanova, P.M. Sinet, M. Vekemans, T. Attie, A.L. Delezoide, J.M. Delabar, Regional and cellular specificity of the expression of TPRD, the tetratricopeptide Down syndrome gene, during human embryonic development, Mech. Dev. 93 (2000) 189--193]. In embryonic stages, SIM2 was identified predominantly in restricted regions of CNS, in ventral part of D1/D2 diencephalic neuroepithelium, along the neural tube and in a few cell subsets of dorsal root ganglia. In fetal stages, SIM2 showed differential expression in pyramidal and granular cell layers of hippocampal formation, in cortical cells and in cerebellar external granular and Purkinje cell layers. SIM2 expression in embryonic and fetal brain could suggest a potential role in human CNS development, in agreement with Drosophila and mouse Sim mutant phenotypes and with the conservation of the Sim function in CNS development from Drosophila to Human. SIM2 expression in human fetal brain regions, which correspond to key structures for cognitive processes, correlates well with the behavioral phenotypes of Drosophila Sim mutants and transgenic mice overexpressing Sim2. In addition, SIM2-expressing brain regions correspond to the altered structures in DS patients. All together, these findings suggest a potential role of SIM2 in CNS development and indicate that SIM2 overexpression could participate to the pathogenesis of mental retardation in Down syndrome patients.

The highly ordered assembly of retinal axons and their synaptic partners is regulated by Hedgehog/Single-minded in theDrosophilavisual system

“…Sim2 maps to the region responsible for Down Syndrome (DS) on Chromosome 21 (Chrast et al, 1997;Dahmane et al, 1995;Muenke et al, 1995). Interestingly, Sim2 is also expressed in non-neuronal tissues, including branchial arches and the developing limb, which are primordia of tissues and organs where DS abnormalities are frequently observed (Rachidi et al, 2005).…”

“…However, because of a lack of direct evidence and the existence of other candidate genes (Antonarakis et al, 2004), this remains speculative. Cells expressing sim during Drosophila development and Sim2-positive cells affected in DS seem to be able to migrate (Rachidi et al, 2005). The conserved role of Sim may enable cells to migrate and/or interact with surrounding cells in the various tissues, including the central nervous system.…”

Increased Expression of SIM2-s Protein Is a Novel Marker of Aggressive Prostate Cancer

“…Proteins encoded by the SIM2 gene belong to a family of transcriptional repressors (3,4) and may control brain development and neuronal differentiation (5,6). In animal studies, SIM2 À/À knockout mice died following craniofacial abnormalities (7) and respiratory failure (8).…”

The molecular pathogenesis of down syndrome-associated diseases and the promising potential therapeutic targets

“…TIAM1 mRNA and protein levels were significantly elevated in 9 human hepatoma cell lines compared to the normal primary human hepatocyte suggesting that TIAM1 overexpression in malignant neoplasms could be a novel effective biomarker for tumors including hepatocellular carcinoma [11]. TIAM1 expression is frequently up-regulated in breast cancer and correlated with clinicopathological parameters, suggesting that TIAM1 may be a useful prognostic biomarker and potential therapeutic target for patients with breast cancer [12].The chromosome 21 gene SIM2 (single minded 2) is one member of transcriptional repressors family involved in the neuronal differentiation and cell growth [13]. The overexpression of SIM2 was associated with tumors of the colon, pancreas and prostate [14,15].…”

“…The chromosome 21 gene SIM2 (single minded 2) is one member of transcriptional repressors family involved in the neuronal differentiation and cell growth [13]. The overexpression of SIM2 was associated with tumors of the colon, pancreas and prostate [14,15].…”