The lack of easily measurable biomarkers remains a challenge in executing clinical trials for diabetic neuropathy (DN). Plasma Neurofilament light chain (NFL) concentration is a promising biomarker in immune-mediated neuropathies. Longitudinal studies evaluating NFL in DN have not been performed.

In the Dp16 mouse model, the Crnic Institute recently showed that normalization of copy number of the Ifnr cluster prevented heart malformations, but the mechanisms by which hyperactive IFN signaling may disrupt normal heart development await elucidation.

The Crnic Institute reports an analysis of the impact of cell differentiation on the p53 transcriptional network using computational studies of large-scale datasets from hundreds of normal tissues and cancer cell types, and an isogenic system consisting of human iPSCs and two differentiated lineages. The results demonstrate that cell differentiation strongly modifies the p53 transcriptional program in a lineage-specific fashion through two major mechanisms: gene silencing by epigenetic regulatory complexes and constitutive transactivation by lineage-specific transcription factors. In differentiated cell types, hundreds of potential p53 target genes become refractory to p53 action either by silencing or constitutive induction. Altogether, the results reveal the vast impact of cell differentiation on the p53 transcriptional program, supporting the notion that p53 may exert its anti-tumoral effects by different mechanisms in diverse cellular contexts.

The authors use human trisomy and tetrasomy 21 cell lines and a mouse model to examine the effects of an additional copy of Pericentrin (PCNT) on cell biology, with a focus on ciliation and ciliary Hedgehog signaling. They demonstrate that modestly increased PCNT levels can attenuate ciliogenesis and may result in trisomy 21-associated phenotypes such as cerebellar growth defects. This work advances our understanding of the trafficking defects caused by increased PCNT and has important implications for our understanding of the cellular basis of trisomy 21, a major hereditary human disorder.

A new study by the Crnic Institute links growth factor deficiency to neurological impairment in Down Syndrome.

The team compared ciliated and unciliated RPE-1 cells with modified HSA21 dosage to show elevated levels of PCNT, an HSA21 resident gene up-regulated in Down syndrome, increases the number of enlarged ectopic PCNT foci peripheral to the centrosome (Figure 4M). These foci disrupt the formation of primary cilia by associating with MTs away from the centrosome, by generating MT dead ends, and by preventing the normal distribution of the centriolar satellites required for efficient ciliogenesis by acting as roadblocks along MTs. They suggest that this disrupts the movement of trafficking events from the cytoplasm to the centrosome by blocking cargo recruitment to mother centriole appendages and the cilium. Further studies will uncover the trafficking dynamics and molecules responsible for ciliary formation and signaling defects. Resetting MT distributions via depolymerization or reducing the number of enlarged PCNT foci allows for normal trafficking and for primary cilia formation. Future work will explore which components are waylaid in the pericentrosomal crowd and their dynamics during trafficking. Moreover, they envision that dysregulated MTs and trafficking could also impact cell types like pancreatic β cells that rely on massive changes to the interphase MT array for signaling and secretion

Individuals with Down Syndrome experience numerous changes in early brain development, including the proliferation and differentiation of neural progenitor cells (NPCs) and the formation and maintenance of myelin in the brain. To study how early neural precursors are affected by trisomy 21, the team differentiated two isogenic lines of induced pluripotent stem cells derived from people with Down syndrome into brain-like and spinal cord-like NPCs and promoted a transition towards oligodendroglial fate by activating the Sonic hedgehog (SHH) pathway.