Impaired subgranular zone radial glia morphology and transient amplification of neural progenitors in <i>Mllt11</i> -deficient mice leads to increased hippocampal neurogenesis
Bibliographic record
Abstract
Abstract The mammalian hippocampus derives from the cortical hem region of the forebrain and is one of the two regions in the mammalian forebrain that contains neural progenitors capable of generating new neurons in the postnatal brain. Hippocampal neural stem cells, referred to as type I progenitors, are Sox2 + /GFAP + , localize along the hilar boundary region, and possess a radial glia fiber that spans the thickness of the dentate gurus. The hilar boundary region serves as a niche for the neural progenitor pool, controlling the activation of type-1 progenitors to transit amplifying type-2 neural progenitors which lose their apical adherence to the hilus as they differentiate to granule cells. The genetic regulation of this process is not fully understood and requires factors that control the mobilization of type-1 cells from their hilar niche in the subgranular zone. To that end we now report a role for Mllt11 (Af1q/Tcf7c; Myeloid/lymphoid or mixed-lineage leukemia; translocated to chromosome 11/All1 Fused Gene from Chromosome 1q/T cell factor 7 co-factor), a regulator of neurite formation and migration in the cortex, in the regulation of hippocampal neurogenesis by restricting the transition of type-1 cells to transit amplifiers and neuroblasts. We previously showed that Cux2 (Cutl2) is widely expressed in the developing hippocampus, initially in the subventricular zone of the cortical hem, which generates the dentate gyrus, then in both type-1 and type-2 neural progenitors, and later in maturing granule cells of the perinatal hippocampus. To evaluate a role for Mllt11 in hippocampal neurogenesis, we used a Cux2 IRESCre/+ line to generate a Mllt11 loss-of-function in perinatal hippocampal progenitors and differentiating granule cells. The loss of Mllt11 led to enlarged dentate blades dues to increased generation of NeuN + and Calbindin + granule cells. Explorations of the progenitor pool revealed increased transit amplifying cells due to an expanded pool of displaced Sox2 + /GFAP + deep in the dentate blades, with altered radial glial morphology. Consequently, type-1 progenitors aberrantly transitioned to amplifying progenitors and neuroblasts, resulting in enhanced granule cell neurogenesis in the postnatal hippocampus. Primary neurosphere formation assays confirmed enhanced proliferation of neural stem cells derived from Mllt11 knockout hippocampi. Taken together, the findings reported here demonstrate the critical role of Mllt11 in maintaining the hippocampal radial glial phenotype and their association within the subgranular zone-hilar niche boundary region, thereby controlling their differentiation to transit amplifiers and granule cells.
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How this classification was reachedexpand
Full frame machine prediction
Teacher imitationNot calibrated prevalence, not ground truth. Human validation pending. The Gemma side is a direct model label for every work in the frame, read from the title-only record. The Codex side is a classifier learned from the 10,348 direct Codex labels and calibrated to design-weighted sample rates; fields without enough sample support carry no Codex call. Candidate is the union of the two sides; consensus is their intersection. These outputs are machine_predicted_unvalidated and are not human labels.
Distilled classifier scores by category (both heads)
| Category | Codex | Gemma |
|---|---|---|
| Metaresearch | 0.000 | 0.000 |
| Meta-epidemiology (narrow) | 0.001 | 0.001 |
| Meta-epidemiology (broad) | 0.000 | 0.001 |
| Bibliometrics | 0.001 | 0.000 |
| Science and technology studies | 0.000 | 0.001 |
| Scholarly communication | 0.001 | 0.000 |
| Open science | 0.001 | 0.001 |
| Research integrity | 0.001 | 0.002 |
| Insufficient payload (model declined to judge) | 0.004 | 0.001 |
Machine scores (provisional)
The two teacher heads of the student model, read on this work. A score orders the frame for review; it never asserts a category, and the validation status ships verbatim with every row.
Baseline scores from an immature model (maturity gate not passed, 7 training rounds). Scores rank; they never assert a category.
score_only:v0-immature-baseline · verbatim from the scoring run: score_only means the number may rank works, and no category label ships from itClassification
machine, unvalidatedMachine predicted; a candidate call from one source (direct Gemma or distilled Codex), not a consensus.
How this classification was reached, model by model and score by score, is at the end of the page under "How this classification was reached".