Mouse embryonic stem cells can differentiate via multiple paths to the same state

Author:

Briggs James Alexander1ORCID,Li Victor C1,Lee Seungkyu23,Woolf Clifford J23,Klein Allon1,Kirschner Marc W1ORCID

Affiliation:

1. Department of Systems Biology, Harvard Medical School, Boston, United States

2. Department of Neurobiology, Harvard Medical School, Boston, United States

3. FM Kirby Neurobiology Center, Boston Children's Hospital, Boston, United States

Abstract

In embryonic development, cells differentiate through stereotypical sequences of intermediate states to generate particular mature fates. By contrast, driving differentiation by ectopically expressing terminal transcription factors (direct programming) can generate similar fates by alternative routes. How differentiation in direct programming relates to embryonic differentiation is unclear. We applied single-cell RNA sequencing to compare two motor neuron differentiation protocols: a standard protocol approximating the embryonic lineage, and a direct programming method. Both initially undergo similar early neural commitment. Later, the direct programming path diverges into a novel transitional state rather than following the expected embryonic spinal intermediates. The novel state in direct programming has specific and uncharacteristic gene expression. It forms a loop in gene expression space that converges separately onto the same final motor neuron state as the standard path. Despite their different developmental histories, motor neurons from both protocols structurally, functionally, and transcriptionally resemble motor neurons isolated from embryos.

Funder

National Institutes of Health

Harvard Brain Initiative

Publisher

eLife Sciences Publications, Ltd

Subject

General Immunology and Microbiology,General Biochemistry, Genetics and Molecular Biology,General Medicine,General Neuroscience

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