Olfactory stem cells reveal MOCOS as a new player in autism spectrum disorders.

With an onset under the age of 3 years, autism spectrum disorders (ASDs) are now understood as diseases arising from pre- and/or early postnatal brain developmental anomalies and/or early brain insults. To unveil the molecular mechanisms taking place during the misshaping of the developing brain, we chose to study cells that are representative of the very early stages of ontogenesis, namely stem cells. Here we report on MOlybdenum COfactor Sulfurase (MOCOS), an enzyme involved in purine metabolism, as a newly identified player in ASD. We found in adult nasal olfactory stem cells of 11 adults with ASD that MOCOS is downregulated in most of them when compared with 11 age- and gender-matched control adults without any neuropsychiatric disorders. Genetic approaches using in vivo and in vitro engineered models converge to indicate that altered expression of MOCOS results in neurotransmission and synaptic defects. Furthermore, we found that MOCOS misexpression induces increased oxidative-stress sensitivity. Our results demonstrate that altered MOCOS expression is likely to have an impact on neurodevelopment and neurotransmission, and may explain comorbid conditions, including gastrointestinal disorders. We anticipate our discovery to be a fresh starting point for the study on the roles of MOCOS in brain development and its functional implications in ASD clinical symptoms. Moreover, our study suggests the possible development of new diagnostic tests based on MOCOS expression, and paves the way for drug screening targeting MOCOS and/or the purine metabolism to ultimately develop novel treatments in ASD.

Differential regulation of Dlg1, Scrib, and Lgl1 expression in a transgenic mouse model of ocular cancer.

PURPOSE: Discs large (dlg), scribble (scrib), and lethal giant larvae (lgl) are major suppressor genes in Drosophila melanogaster. They encode proteins that regulate cell polarity and cell proliferation in Drosophila and mammals. However, their basic oncogenic roles have not yet been established in mouse epithelial ocular cancer. We evaluated the potential implication of these proteins in tumorigenesis of adenocarcinomas originating from the retinal pigmented epithelium of the Trp1/Tag transgenic mouse model. We examined the changes in the distribution and levels of these proteins in mouse ocular tissues from the Trp1/Tag mouse model. METHODS: The expression patterns of theses genes and their corresponding proteins in normal mouse ocular tissues were studied by in situ hibridization and immunohistofluorescence experiments. In addition, variations in mRNA and proteins levels and protein distributions for Dlg1, Scrib, and Lgl1 were analyzed in the ocular tissues from Trp1/Tag transgenic mouse model by reverse transcription polymerase chain reaction (RT-PCR), western blot analysis, and immunohistofluorescence. RESULTS: We found that mouse Dlg1, Scrib, and Lgl1 are widely distributed in normal ocular tissues, particularly in retinal neurons. We found that the three proteins are mislocalized in retinal layers during ocular carcinogenesis. These mislocalizations were correlated to the early dysplastic stages of ocular tumorigenesis. Additionally, the mislocalization of each protein was associated with its downregulation. Decreased levels of these proteins may be considered as late-stage markers of the disease but also as markers of the invasive stage of this cancerous process. This downregulation may be involved in epithelial-mesenchymal transition in this mouse ocular tumoral model. This would be consistent with the downregulation of E-cadherin and upregulation of N-cadherin expression observed in this model. CONCLUSIONS: This is the first study to demonstrate the involvement of Dlg1, Scrib, and Lgl1 in a mouse with ocular adenocarcinoma and the simultaneous involvement of these proteins in the same cancer. Our results indicate that both the mislocalization and downregulation of these proteins may be involved together in ocular carcinogenesis.

Analysis of partner of inscuteable (mPins) expression in the developing mouse eye.

PURPOSE: Asymmetric cell division (ACD) is the fundamental mechanism underlying the generation of cellular diversity in invertebrates and vertebrates. During Drosophila neuroblast division, this process involves stabilization of the apical complex and interaction between the Inscuteable (Insc) and Partner of inscuteable (Pins) proteins. Both cell-intrinsic factors and cell-cell interactions seem to contribute to cell fate decisions in the retina. The Pins protein is known to play a major role in the asymmetric segregation of cell fate determinants during development of the central nervous system in general, but its role in asymmetric cell divisions and retinoblast cell fate has never been explored. The primary aim of this study was to determine the spatial distribution and time course of mouse homolog of Drosophila Partner of Inscuteable (mPins) expression in the developing and adult mouse eye. METHODS: The expression pattern of mPins was studied in the mouse eye from embryonic (E) stage E11.5 until adulthood, by semiquantitative RT-PCR, in situ hybridization, and immunohistochemistry. In addition, variations in mRNA and protein levels for mPins were analyzed in the developing postnatal and adult lens, by semiquantitative RT-PCR, western blot analysis, in situ hybridization, and immunohistochemistry. RESULTS: We detected mPins mRNA at early stages of mouse embryonic eye development, particularly in the neuroblastic layer. In early postnatal development, mPins mRNA was still detected in the neuroblastic layer, but also began to be detectable in the ganglion cell layer. Thereafter, mPins mRNA was found throughout the retina. This pattern was maintained in differentiated adult retina. Immunohistochemical studies showed that mPins protein was present in the neuroblastic layer and the ganglion cell layer during the early stages of postnatal retinal development. At these stages, mPins protein was colocalized with Numb protein, a marker of the ACD. At later postnatal stages, mPins protein was present in all retinal nuclear layers and in the inner plexiform layer. It continued to be detected in these layers in the differentiated retina; the outer plexiform layer and the photoreceptor inner segments also began to display positive immunostaining for mPins. In the adult retina, mPins was also detected in the retinal pigment epithelium and choroidal melanocytes. Throughout development, mPins protein was detected in nonretinal tissues, including the cornea, ciliary body, and lens. We focused our attention on lens development and showed that mPins protein was first detected at E14.5. The most striking results obtained concerned the lens, in which mPins protein distribution switched from the anterior to the posterior region of the lens during embryonic development. Interestingly, in the postnatal and adult lens, mPins protein was detected in all lens cells and fibers. CONCLUSIONS: We provide the first demonstration that mPins protein is expressed from embryonic stages until adulthood in the mouse eye. These results suggest that mPins plays important roles in eye development. This work provides preliminary evidence strongly supporting a role for mPins in the asymmetric division of retinoblasts, and in the structure and functions of adult mouse retina. However, the link between the presence of mPins in different ocular compartments and the possible occurrence of asymmetric cell divisions in these compartments remains to be clarified. Further studies are required to elucidate the in vitro and in vivo functions of mPins in the developing and adult human eye.