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An isogenic human iPSC model unravels neurodevelopmental abnormalities in SMA

ABSTRACT: Whether neurodevelopmental defects underlie the selective neuronal death that characterizes neurodegenerative diseases is becoming an intriguing question. To address it, we focused on the motor neuron (MN) disease Spinal Muscular Atrophy (SMA), caused by reduced levels of the ubiquitous protein SMN. Taking advantage of the first isogenic human induced pluripotent stem cell-derived SMA model that we have generated and a spinal cord organoid system, here we report that the relative and temporal expression of early neural progenitor and MN markers is altered in SMA. Furthermore, the corrected isogenic controls only partially reverse these abnormalities. These findings raise the relevant clinical implication that SMN-increasing treatments might not fully amend SMA pathological phenotypes. The approach we have taken demonstrates that the discovery of new disease mechanisms is greatly improved by using human isogenic models. Moreover, our study implies that SMA has a developmental component that might trigger the MN degeneration.

PROVIDER: EGAS00001007259 | EGA |

REPOSITORIES: EGA

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Project description:Motor neuron (MN), together with interneuron, are the two major neuronal types in spinal cord. MNs control muscle movement and are essential for breathing, walking and fine motor skills. Malfunction of MNs is frequently associated with neuronal diseases such as spinal muscular atrophy and amyotrophic lateral sclerosis. To establish normal function, MNs need to be differentiated properly from neural progenitor cells. Thus, it is of great importance to study the mechanism for MN specification. This study focuses on Mnx1 - a conserved homeobox transcription factor gets expressed during MN specification. Mnx1 is also the most widely used MN marker. Previous studies reported that Mnx1 mutation in mouse causes early lethality - probably by affecting the controlling over respiratory system. However, the exact role of Mnx1 for MN identity remains poorly understood. Taking advantage of a recently developed in vitro model for efficient MN induction from mouse ES cells, we combined experimental and OMICs techniques to systematically investigate the molecular function of Mnx1. We identified thousands of Mnx1 binding sites - many are co-bound by core MN factor Lhx3 and Isl1 and lack active histone marks. Disruption of Mnx1 causes increased expression of 85 genes - while only 14 genes get down-regulated. Up-regulated genes are enriched with neuronal functions, usually get expressed during MN differentiation, and tend to have higher expression in motor neurons and brain compared with other tissues – indicating Mnx1 may fine tune neuronal genes to desired level. However, only a dozen of regions with increased H3K27ac marks are bound by Mnx1, and only two up-regulated genes (Pbx3 and Pou6f2) are identified as putative direct targets of Mnx1 - both are core neuronal factors with the potential to regulate other differential neuronal genes. These results suggest that Mnx1 may contribute to MN identity by fine-tuning the expression of many neuronal genes through direct regulation of a few core neuronal transcription factors. In summary, this study represents the first systematic investigation about the molecular function of the core MN factor Mnx1. It clarifies the mechanism of Mnx1 for MN identity, and also improves the understanding about the regulation mode of homeobox transcription factors.

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An isogenic human iPSC model unravels neurodevelopmental abnormalities in SMA

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