Subventricular zone stem cells are heterogeneous with respect to their embryonic origins and neurogenic fates in the adult olfactory bulb

Wedetermined the embryonic origins of adult forebrain subventricular zone (SVZ) stem cells by Cre-lox fate mapping in transgenic mice. We found that all parts of the telencephalic neuroepithelium, including the medial ganglionic eminence and lateral ganglionic eminence (LGE) and the cerebral cortex, contribute multipotent, self-renewing stem cells to the adult SVZ. Descendants of the embryonic LGE and cortex settle in ventral and dorsal aspects of the dorsolateral SVZ, respectively. Both populations contribute new (5-bromo-2(')-deoxyuridine- labeled) tyrosine hydroxylase- and calretinin-positive interneurons to the adult olfactory bulb. However, calbindin-positive interneurons in the olfactory glomeruli were generated exclusively by LGE- derived stem cells. Thus, different SVZ stem cells have different embryonic origins, colonize different parts of the SVZ, and generate different neuronal progeny, suggesting that some aspects of embryonic patterning are preserved in the adult SVZ. This could have important implications for the design of endogenous stem cell-based therapies in the future

Genetic programs controlling cortical interneuron fate.

The origins of cortical interneurons in rodents have been localized to the embryonic subcortical telencephalon where distinct neuroepithelial precursors generate defined interneuron subsets. A swathe of research activity aimed at identifying molecular determinants of subtype identity has uncovered a number of transcription factors that function at different stages of interneuron development. Pathways that lead to the acquisition of mature interneuron traits are therefore beginning to emerge. As genetic programs are influenced by external factors the search continues not only into genetic determinants but also extrinsic influences and the interplay between the two in cell fate specification

Hippocampal CA1 Somatostatin Interneurons Originate in the Embryonic MGE/POA

Oriens lacunosum-moleculare (O-LM) interneurons constitute 40% of hippocampal interneurons expressing Somatostatin (SST). Recent evidence has indicated a dual origin for these cells in the medial and caudal ganglionic eminences (MGE and CGE), with expression of Htr3a as a distinguishing factor. This is strikingly different from cortical SST interneurons that have a single origin within the MGE/preoptic area (POA). We reassessed the origin of hippocampal SST interneurons using a range of genetic lineage-tracing mice combined with single-cell transcriptomic analysis. We find a common origin for all hippocampal SST interneurons in NKX2-1-expressing progenitors of the telencephalic neuroepithelium and an MGE/POA-like transcriptomic signature for all SST clusters. This suggests that functional heterogeneity within the SST CA1 population cannot be attributed to a differential MGE/CGE genetic origin

NKX2-1 Is Required in the Embryonic Septum for Cholinergic System Development, Learning, and Memory

The transcription factor NKX2-1 is best known for its role in the specification of subsets of cortical, striatal, and pallidal neurons. We demonstrate through genetic fate mapping and intersectional focal septal deletion that NKX2-1 is selectively required in the embryonic septal neuroepithelium for the development of cholinergic septohippocampal projection neurons and large subsets of basal forebrain cholinergic neurons. In the absence of NKX2-1, these neurons fail to develop, causing alterations in hippocampal theta rhythms and severe deficiencies in learning and memory. Our results demonstrate that learning and memory are dependent on NKX2-1 function in the embryonic septum and suggest that cognitive deficiencies that are sometimes associated with pathogenic mutations in NKX2-1 in humans may be a direct consequence of loss of NKX2-1 function

Improved Diagnosis and Management of Paediatric Renal Transplant Recipients Using the Banff 2013 Histopathological Classification

Introduction: Since the publication of the 2013 Banff classification, adult studies have shown evidence of improved prognosis using the new histopathological criteria. Our study assesses for the first time the impact of the new classification on the diagnosis of acute antibody-mediated rejection (AMR) in paediatric renal transplant recipients (pRTR). / Methods: This single-centre study is a retrospective evaluation of 56 paediatric post-transplant de novo DSA-positive patients who had a percutaneous renal transplant biopsy due to renal allograft dysfunction from January 2006 to March 2012. Their biopsies were re-scored by a solitary specialist trained in 2013 Banff classification. The results were compared with previous classification as per 2003/2007 Banff criteria with results presented as range (median). / Results: At the time of biopsy, pRTR were aged 1.6 - 17.5 (median 14.9) years old with 412 - 2735 mean fluorescence intensity (MFI; maximal at 713 - 31,625; median 3466 and 4809). Following the 2013 Banff classification, there was a total of 5 cases of acute AMR compared to one confirmed and one suspicious AMR with the 2003/2007 Banff classification (with no change in the remaining 51 patients’ classification). Consequently, 5.3% (3 of 56) patients would have been diagnosed with T-cell mediated rejection with suboptimal treatment. There was an overall 70% (48 - 112%) decrease in the renal allograft function in the 6 months follow-up period after aggressive treatment for acute AMR and 2 of 3 patients had further rejection episodes in the following year. / Conclusion: This research supports the new Banff 2013 classification as a more precise classification in pRTR in the diagnosis of AMR with 5% of patients being correctly diagnosed and managed with improvement in renal allograft function

Desensitization protocol enabling pediatric crossmatch-positive renal transplantation: successful HLA-antibody-incompatible renal transplantation of two highly sensitized children

BACKGROUND: Renal transplantation improves quality of life (QoL) and survival in children requiring renal replacement therapy (RRT). Sensitization with development of a broad-spectrum of anti-HLA antibodies as a result of previous transplantation or after receiving blood products is an increasing problem. There are no published reports of desensitization protocols in children allowing renal transplantation from HLA-antibody-incompatible living donors. METHODS: We adopted our well-established adult desensitization protocol for this purpose and undertook HLA antibody-incompatible living donor renal transplants in two children: a 14-year-old girl and a 13-year-old boy. RESULTS: After 2 and 1.5 years of follow-up, respectively, both patients have stable renal allograft function despite a rise in donor-specific antibodies in one case. CONCLUSIONS: HLA-incompatible transplantation should be considered in selected cases for sensitized children

Utilisation of small paediatric donor kidneys for transplantation

With the increasing need for kidney transplantation in the paediatric population and changing donor demographics, children without a living donor option will potentially be offered an adult deceased donor transplant of marginal quality. Given the importance of long-term graft survival for paediatric recipients, consideration is now being given to kidneys from small paediatric donors (SPDs). There exist a lack of consensus and a reluctance amongst some centres in transplanting SPDs due to high surgical complication rates, graft loss and concerns regarding low nephron mass and long-term function. The aim of this review is to examine and present the evidence base regarding the transplantation of these organs. The literature in both the paediatric and adult renal transplant fields, as well as recent relevant conference proceedings, is reviewed. We discuss the surgical techniques, long-term graft function and rates of complications following transplantation of SPDs. We compare graft survival of SPDs to adult deceased donors and consider the use of small paediatric donors after circulatory death (DCD) organs. In conclusion, evidence is presented that may refute historically held paradigms regarding the transplantation of SPDs in paediatric recipients, thereby potentially allowing significant expansion of the donor pool

MTG8 interacts with LHX6 to specify cortical interneuron subtype identity

Cortical interneurons originating in the embryonic medial ganglionic eminence (MGE) diverge into a range of different subtypes found in the adult mouse cerebral cortex. The mechanisms underlying this divergence and the timing when subtype identity is set up remain unclear. We identify the highly conserved transcriptional co-factor MTG8 as being pivotal in the development of a large subset of MGE cortical interneurons that co-expresses Somatostatin (SST) and Neuropeptide Y (NPY). MTG8 interacts with the pan-MGE transcription factor LHX6 and together the two factors are sufficient to promote expression of critical cortical interneuron subtype identity genes. The SST-NPY cortical interneuron fate is initiated early, well before interneurons migrate into the cortex, demonstrating an early onset specification program. Our findings suggest that transcriptional co-factors and modifiers of generic lineage specification programs may hold the key to the emergence of cortical interneuron heterogeneity from the embryonic telencephalic germinal zones

Long-range projections from sparse populations of GABAergic neurons in murine subplate

The murine subplate contains some of the earliest generated populations of neurons in the cerebral cortex, which play an important role in the maturation of cortical inhibition. Here we present multiple lines of evidence, that the subplate itself is only very sparsely populated with GABAergic neurons at postnatal day (P)8. We used three different transgenic mouse lines, each of which labels a subset of GABAergic, ganglionic eminence derived neurons. Dlx5/6-eGFP labels the most neurons in cortex (on average 11% of NEUN+ cells across all layers at P8) whereas CGE-derived Lhx6-Cre::Dlx1-Venusfl cells are the sparsest (2% of NEUN+ cells across all layers at P8). There is significant variability in the layer distribution of labelled interneurons, with Dlx5/6-eGFP and Lhx6-Cre::R26R-YFP being expressed most abundantly in layer 5, whereas CGE-derived Lhx6-Cre::Dlx1-Venusfl cells are least abundant in that layer. All three lines label at most 3% of NEUN+ neurons in the subplate, in contrast to L5, in which up to 30% of neurons are GFP+ in Dlx5/6-eGFP. We assessed all three GABAergic populations for expression of the subplate neuron marker connective tissue growth factor (CTGF). CTGF labels up to two thirds of NeuN+ cells in the subplate, but was never found to co-localise with labelled GABAergic neurons in any of the three transgenic strains. Despite the GABAergic neuronal population in the subplate being sparse, long-distance axonal connection tracing with carbocyanine dyes revealed that some Gad65-GFP+ subplate cells form long-range axonal projections to the internal capsule or callosum