Induced Neurons From Germ Cells in Caenorhabditis elegans

Abstract

Cell fate conversion by the forced overexpression of transcription factors (TFs) is a process known as reprogramming. It leads to de-differentiation or trans-differentiation of mature cells, which could then be used for regenerative medicine applications to replenish patients suffering from, e.g., neurodegenerative diseases, with healthy neurons. However, TF-induced reprogramming is often restricted due to cell fate safeguarding mechanisms, which require a better understanding to increase reprogramming efficiency and achieve higher fidelity. The germline of the nematode Caenorhabditis elegans has been a powerful model to investigate the impediments of generating neurons from germ cells by reprogramming. A number of conserved factors have been identified that act as a barrier for TF-induced direct reprogramming of germ cells to neurons. In this review, we will first summarize our current knowledge regarding cell fate safeguarding mechanisms in the germline. Then, we will focus on the molecular mechanisms underlying neuronal induction from germ cells upon TF-mediated reprogramming. We will shortly discuss the specific characteristics that might make germ cells especially fit to change cellular fate and become neurons. For future perspectives, we will look at the potential of C. elegans research in advancing our knowledge of the mechanisms that regulate cellular identity, and what implications this has for therapeutic approaches such as regenerative medicine.

The Impact of Hormesis, Neuronal Stress Response, and Reproduction, upon Clinical Aging: A Narrative Review

“…Germline cells have the innate capacity to become neurons following suitable natural (or artificial) reprogramming by transcription factors, even though there are several conserved mechanisms that safeguard against this. This is an intriguing situation because it shows the direct relationship between the germline and the brain [ 103 ]. In addition, multipotent neural and glial precursors can be derived from multipotent adult germ line stem cells [ 104 ].…”

“… Germline cells have the capacity to become neurons. Neural precursors from the germline are able to mature and integrate within the existing neural network [ 103 , 104 , 105 , 106 , 107 ]. A direct communication pathway between germline cells and the soma depends on the endoplasmic reticulum stress factor inositol requiring enzyme-1 (IRE-1) [ 110 ].…”

Recent advances and current challenges of new approach methodologies in developmental and adult neurotoxicity testing

“…About the endpoints addressed by the DNT IVB (reported in Table 5 ), implementing a similar battery of tests using C. elegans is yet to be developed. The study of neuronal cell proliferation from stem cells in C. elegans is well-established (Marchal and Tursun 2021 ). When reprogramming barriers like chromatin regulators are removed, germ cells can be reprogrammed to specific neuron subtypes (Kolundzic et al 2018 ).…”

Identifying Molecular Roadblocks for Transcription Factor-Induced Cellular Reprogramming In Vivo by Using C. elegans as a Model Organism

“…Several barrier factors for TF-induced reprogramming were identified in C. elegans and have a high degree of conservation. Notably, some were also shown to block TF-induced reprogramming in mammalian cells [ 10 , 11 ], indicating the power of C. elegans -based investigation of cellular reprogramming dynamics.…”