Mutations in the gene encoding FERM domain-containing 7 protein (FRMD7) are recognized as an important cause of X-linked idiopathic infantile nystagmus (IIN). However, the precise role of FRMD7 and its involvement in the pathogenesis of IIN are not understood. In the present study, we have explored the role of FRMD7 in neuronal development. Using in situ hybridization and immunohistochemistry, we reveal that FRMD7 expression is spatially and temporally regulated in both the human and mouse brain during embryonic and fetal development. Furthermore, we show that FRMD7 expression is up-regulated upon retinoic acid (RA)-induced differentiation of mouse neuroblastoma NEURO2A cells, suggesting FRMD7 may play a role in this process. Indeed, we demonstrate, for the first time, that knockdown of FRMD7 during neuronal differentiation results in altered neurite development. Taken together, our data suggest that FRMD7 is involved in multiple aspects of neuronal development, and have direct importance to further understanding the pathogenesis of IIN.

Mutations of thymidine kinase 2 (TK2), an essential component of the mitochondrial nucleotide salvage pathway, can give rise to mitochondrial DNA (mtDNA) depletion syndromes (MDS). These clinically heterogeneous disorders are characterized by severe reduction in mtDNA copy number in affected tissues and are associated with progressive myopathy, hepatopathy and/or encephalopathy, depending in part on the underlying nuclear genetic defect. Mutations of TK2 have previously been associated with an isolated myopathic form of MDS (OMIM 609560). However, more recently, neurological phenotypes have been demonstrated in patients carrying TK2 mutations, thus suggesting that loss of TK2 results in neuronal dysfunction. Here, we directly address the role of TK2 in neuronal homeostasis using a knockout mouse model. We demonstrate that in vivo loss of TK2 activity leads to a severe ataxic phenotype, accompanied by reduced mtDNA copy number and decreased steady-state levels of electron transport chain proteins in the brain. In TK2-deficient cerebellar neurons, these abnormalities are associated with impaired mitochondrial bioenergetic function, aberrant mitochondrial ultrastructure and degeneration of selected neuronal types. Overall, our findings demonstrate that TK2 deficiency leads to neuronal dysfunction in vivo, and have important implications for understanding the mechanisms of neurological impairment in MDS.

The promyeloctic leukemia protein PML is a tumor suppressor that was originally identified due to its involvement in the (15;17) translocation of acute promyelocytic leukemia. While the majority of early research has focused upon the role of PML in the pathogenesis of leukemia, more recent evidence has identified important roles for PML in tissues outside the hemopoietic system, including the central nervous system (CNS). Here, we review recent literature on the role of PML in the CNS, with particular focus on the processes of neurodevelopment and neurodegeneration, and propose new lines of investigation.