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BackgroundA goal of developmental genetics is to identify functional interactions that underlie phenotypes caused by mutations. We sought to identify functional interactors of Vsx2, which when mutated, disrupts early retinal development. We utilized the Vsx2 loss‐of‐function mouse, ocular retardation J (orJ), to assess interactions based on principles of positive and negative epistasis as applied to bulk transcriptome data. This was first tested in vivo with Mitf, a target of Vsx2 repression, and then to cultures of orJ retina treated with inhibitors of Retinoid‐X Receptors (RXR) to target Rxrg, an up‐regulated gene in the orJ retina, and gamma‐Secretase, an enzyme required for Notch signaling, a key mediator of retinal proliferation and neurogenesis.ResultsWhereas Mitf exhibited robust positive epistasis with Vsx2, it only partially accounts for the orJ phenotype, suggesting other functional interactors. RXR inhibition yielded minimal evidence for epistasis between Vsx2 and Rxrg. In contrast, gamma‐Secretase inhibition caused hundreds of Vsx2‐dependent genes associated with proliferation to deviate further from wild‐type, providing evidence for convergent negative epistasis with Vsx2 in regulating tissue growth.ConclusionsCombining in vivo and ex vivo testing with transcriptome analysis revealed quantitative and qualitative characteristics of functional interaction between Vsx2, Mitf, RXR, and gamma‐Secretase activities.

Cerebrospinal fluid (CSF) from twenty three patients with non specific mental retardation and fourteen age matched normal samples was subjected for qualitative analysis of protein profiles by two-dimensional gel electrophoresis (2-DE) and the proteins were visualised by ultra sensitive silver staining. Two proteins designated as mental retardation associated proteins (MRAP-I and MRAP-II) were identified in six male patients out of twenty three patients CSF samples. MRAP-I had an isoelectric point of 7.4 with a relative molecular weight 16.5 kDa, while MRAP-II had an iso-electric point of 7.2 with a relative molecular weight 16.8 kDa. The two proteins are presumed to be originated from brain, as they could not be traced in the serum of patients, nor due to proteolytic degradation. Despite unknown origin and identity, their presence in the CSF of a specific group of mentally retarded male patients suggest their possible clinical utility and to define protein alterations in mental retardation.