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Rizzo, D.

Publications and source records attributed to Rizzo, D..

2 recordsLinked to original sources

Cortical somatostatin interneuron subtypes form cell-type specific circuits

The cardinal interneuron classes are a useful simplification of cortical interneuron diversity, but such broad subgroupings glosses over the molecular, morphological, and circuit specificity of interneuron subtypes, most notably among the somatostatin interneuron class. The organizing principles by which the connectivity of these subtypes is specified are unknown. To address this knowledge gap, we designed a series of genetic strategies to target the breadth of somatostatin interneuron subtypes. Using these strategies to target three subtypes that span the entire cortical column, we examined their afferent and efferent connectivity. Our data demonstrated that each of these possesses remarkable reciprocal connectivity with the intracortical or corticofugal pyramidal classes, as well as parvalbumin interneurons. Even when two interneuron subtypes shared the same efferent target, their synaptic targeting proved selective for particular dendritic compartments. We thus provide evidence that subtypes of somatostatin cortical interneurons form cell-type specific cortical circuits.

neuroscience↗

Increased frequencies of IgH locus suicide recombination points on Chronic Lymphocytic Leukemia with low rate of AID related somatic mutations, cMYC overexpression and short telomeres

In normal activated B-cells, Activation Induced-cytidine deaminase (AID) is absolutely required for immunoglobulin (Ig) class switch recombination (CSR) and IGHV somatic hypermutation (SHM). AID is also implicated in the Locus Suicide Recombination (LSR) of the Ig heavy (IgH) locus, resulting in the deletion of the IgH constant part. Chronic lymphocytic leukemia (CLL) is an indolent non-Hodgkin B-cell lymphoma characterized by tumor CLL B-cells that weakly express a B cell receptor (BCR) on their surface. The great majority of CLL tumor B-cells are non class-switched. Searching for abnormalities of IgH locus recombination in CLL, we investigated CSR and LSR in samples from CLL patients (N=47) with high blood tumor cell infiltration (>98%) and in healthy volunteers (HV) as controls (N=9). LSR was detectable at comparable levels in both HV and CLL groups. CSR counts were decreased in CLL samples as expected. As distribution of LSR counts was bimodal, we separated CLL patients in two groups so called LSRHigh and LSRLow. LSRHigh CLLs exhibited very weak AID expression and low mutation rate of IgHV region and of the AID off-target PIM1 gene. LSR junction diversity, evaluated using the Shannon index, was increased in LSRHigh CLLs suggesting that LSR was on-going in these cells. Also, shorter telomeres were observed in LSRHigh CLLs suggesting an increased number of past mitosis. Consistently, increased levels of cMYC expression were detected in LSRHigh CLLs and treatment free survival of these cases was markedly decreased. We hypothesized that LSR in LSRHigh CLLs is AID independent and could be due to DNA lesion and inaccurate DSB repair within the IgH locus, which could be accessible to recombination machinery due to increased IgH locus transcription. Altogether, our results indicate the accessibility of IgH locus and the proliferation increase LSR rate in LSRHigh CLLs could be related to cMYC resulting in shorter treatment free survival of patients and point on an AID independent mechanism of IgH recombination.

cancer biology↗