MR Imaging in Spinocerebellar Ataxias: A Systematic Review.

BACKGROUND AND PURPOSE: Polyglutamine expansion spinocerebellar ataxias are autosomal dominant slowly progressive neurodegenerative diseases with no current treatment. MR imaging is the best-studied surrogate biomarker candidate for polyglutamine expansion spinocerebellar ataxias, though with conflicting results. We aimed to review quantitative central nervous system MR imaging technique findings in patients with polyglutamine expansion spinocerebellar ataxias and correlations with well-established clinical and molecular disease markers. MATERIALS AND METHODS: We searched MEDLINE, LILACS, and Cochrane data bases of clinical trials between January 1995 and January 2016, for quantitative MR imaging volumetric approaches, MR spectroscopy, diffusion tensor imaging, or other quantitative techniques, comparing patients with polyglutamine expansion spinocerebellar ataxias (SCAs) with controls. Pertinent details for each study regarding participants, imaging methods, and results were extracted. RESULTS: After reviewing the 706 results, 18 studies were suitable for inclusion: 2 studies in SCA1, 1 in SCA2, 15 in SCA3, 1 in SCA7, 1 in SCA1 and SCA6 presymptomatic carriers, and none in SCA17 and dentatorubropallidoluysian atrophy. Cerebellar hemispheres and vermis, whole brain stem, midbrain, pons, medulla oblongata, cervical spine, striatum, and thalamus presented significant atrophy in SCA3. The caudate, putamen and whole brain stem presented similar sensitivity to change compared with ataxia scales after 2 years of follow-up in a single prospective study in SCA3. MR spectroscopy and DTI showed abnormalities only in cross-sectional studies in SCA3. Results from single studies in other polyglutamine expansion spinocerebellar ataxias should be replicated in different cohorts. CONCLUSIONS: Additional cross-sectional and prospective volumetric analysis, MR spectroscopy, and DTI studies are necessary in polyglutamine expansion spinocerebellar ataxias. The properties of preclinical disease biomarkers (presymptomatic) of MR imaging should be targeted in future studies.

Control of midline glia development in the embryonic Drosophila CNS.

The midline glial cells are required for correct formation of the axonal pattern in the embryonic ventral nerve cord of Drosophila. Initially, six midline cells form an equivalence group with the capacity to develop as glial cells. By the end of embryonic development three to four cells are singled out as midline glial cells. Midline glia development occurs in two steps, both of which depend on the activation of the Drosophila EGF-receptor homolog and subsequent ras1/raf-mediated signal transduction. Nuclear targets of this signalling cascade are the ETS domain transcription factors pointedP2 and yan. In the midline glia pointedP2 in turn activates the transcription of argos, which encodes a diffusible negative regulator of EGF-receptor signalling.

Control of midline glia development in the embryonic Drosophila CNS.

The midline glial cells are required for correct formation of the axonal pattern in the embryonic ventral nerve cord of Drosophila. Initially, six midline cells form an equivalence group with the capacity to develop as glial cells. By the end of embryonic development three to four cells are singled out as midline glial cells. Midline glia development occurs in two steps, both of which depend on the activation of the Drosophila EGF-receptor homolog and subsequent ras1/raf-mediated signal transduction. Nuclear targets of this signalling cascade are the ETS domain transcription factors pointedP2 and yan. In the midline glia pointedP2 in turn activates the transcription of argos, which encodes a diffusible negative regulator of EGF-receptor signalling.

EGF receptor signaling induces pointed P1 transcription and inactivates Yan protein in the Drosophila embryonic ventral ectoderm.

The induction of different cell fates along the dorsoventral axis of the Drosophila embryo requires a graded activity of the EGF receptor tyrosine kinase (DER). Here we have identified primary and secondary target genes of DER, which mediate the determination of discrete ventral cell fates. High levels of DER activation in the ventralmost cells trigger expression of the transcription factors encoded by ventral nervous system defective (vnd) and pointed P1 (pntPl). Concomitant with the induction of pntP1, high levels of DER activity lead to inactivation of the Yan protein, a transcriptional repressor of Pointed-target genes. These two antagonizing transcription factors subsequently control the expression of secondary target genes such as otd, argos and tartan. The simultaneous effects of the DER pathway on pntP1 induction and Yan inactivation may contribute to the definition of the border of the ventralmost cell fates.

Function of ets genes is conserved between vertebrates and Drosophila.

The Drosophila pointed gene encodes two ETS transcriptional activators, pointedP1 and pointedP2, sharing a common C-terminal ETS domain. In the embryonic central nervous system pointedP2 is required for midline glial cell differentiation, whereas, in the eye, pointedP2 is essential for photoreceptor cell differentiation. Both vertebrate c-ets-1 and c-ets-2 gene ETS domains are highly homologous to the one of pointed. In addition, the N-terminal region of pointedP2 and vertebrate ets products share another homologous domain, the so-called RII/pointed box which appears to mediate the ras-dependent phosphorylation/stimulation. Here, we show that the vertebrate ets genes are functionally homologous to the Drosophila pointed gene. pointedP2 efficiently binds to an optimized c-Ets-1/c-Ets-2 probe in vitro, and stimulates two distinct c-Ets-1/c-Ets-2-responsive sequences when transiently expressed in vertebrate cells. Conversely, when vertebrate ets transgenes are expressed during fly development, they are capable of rescuing the pointed mutant phenotype in both midline glia and photoreceptor development. As ectopically expressed pointedP1 can also rescue pointedP2 deficiency in photoreceptor development, it appears that the ability of ets products to phenocopy each other in vivo does not require the conserved RII/pointed box, but rather, primarily relies on the presence of the highly conserved ETS domain.

The Ets transcription factors encoded by the Drosophila gene pointed direct glial cell differentiation in the embryonic CNS.

The Drosophila gene pointed (pnt) encodes two putative transcription factors (P1 and P2) of the Ets family, which in the embryonic CNS are found exclusively in glial cells. Loss of pnt function leads to poorly differentiated glial cells and a marked decrease in the expression of the neuronal antigen 22C10 in the MP2 neurons, which are known to interact intimately with the pntP1-expressing longitudinal glial cells. Ectopic expression of pntP1 RNA forces additional CNS cells to enter the glial differentiation pathway. Interestingly, the additional glial-like cells are often flanked by cells that ectopically express the neuronal antigen 22C10. Therefore, both the pnt loss-of-function as well as the gain-of-function phenotype suggest that glial cells are able to induce 22C10 expression on neighboring neurons. This was further verified by cell transplantation experiments. Thus, pnt is not only required but also sufficient for several aspects of glial differentiation.

Genetic dissection of pointed, a Drosophila gene encoding two ETS-related proteins.

The Drosophila gene pointed (pnt) is required for the differentiation of a number of tissues during embryogenesis, including the ventral ectoderm, the nervous system, the tracheal system and certain muscle fibers. The phenotypes associated with strong pointed alleles are reflected by a complex pointed expression pattern during embryogenesis. Two promoters, P1 and P2, separated by some 50 kb of genomic sequences, direct the transcription of two different transcript forms, encoding two different proteins related to the ETS family of transcription factors. To assess the individual functions of the two different pointed protein forms, we have generated new pointed alleles affecting either the P1 or the P2 transcript, termed P1 and P2 alleles, respectively. Genetic analysis reveals partial heteroallelic complementation between certain pointed P1 and P2 alleles. Surviving trans-heterozygous flies have rough eyes, abnormal wings and halters, suggesting a requirement for pointed function during their imaginal disc development. Further genetic analysis demonstrates that expression of a given pointed P2 allele depends on trans-acting transcriptional regulatory sequences. We have identified two chromosomal domains with opposite regulatory effects on the transcriptional activity of the pointed P2 promoter, one trans-activates and the other trans-represses pointed P2 expression. By deletion mapping we were able to localize these control regions within the 5' region of the pointed P2 transcript.