Forced LMX1A expression induces dorsal neural fates and disrupts patterning of human embryonic stem cells into ventral midbrain dopaminergic neurons

Schörling, Alrik (author): Lund University,Lunds universitet,Human neural utvecklingsbiologi,Forskargrupper vid Lunds universitet,Human Neural Developmental Biology,Lund University Research Groups,University of Copenhagen

Wolf, Daniel A. (author): Lund University,Lunds universitet,Neurobiologi,Forskargrupper vid Lunds universitet,Utvecklings- och regenerativ neurobiologi,Neurobiology,Lund University Research Groups,Developmental and Regenerative Neurobiology

Heuer, Andreas (author): Lund University,Lunds universitet,Beteendevetenskapligt laboratorium,Forskargrupper vid Lunds universitet,Behavioural Neuroscience Laboratory,Lund University Research Groups

Kirkeby, Agnete (author): Lund University,Lunds universitet,Human neural utvecklingsbiologi,Forskargrupper vid Lunds universitet,WCMM- Wallenberg center för molekylär medicinsk forskning,Medicinska fakulteten,Human Neural Developmental Biology,Lund University Research Groups,WCMM-Wallenberg Centre for Molecular Medicine,Faculty of Medicine,University of Copenhagen

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Related links:: http://dx.doi.org/10... (free); show more...; https://lup.lub.lu.s...; https://doi.org/10.1...; show less...

Abstract Subject headings

The differentiation of human pluripotent stem cells into ventral mesencephalic dopaminergic (DA) fate is relevant for the treatment of Parkinson's disease. Shortcuts to obtaining DA cells through direct reprogramming often include forced expression of the transcription factor LMX1A. Although reprogramming with LMX1A can generate tyrosine hydroxylase (TH)-positive cells, their regional identity remains elusive. Using an in vitro model of early human neural tube patterning, we report that forced LMX1A expression induced a ventral-to-dorsal fate shift along the entire neuroaxis with the emergence of roof plate fates despite the presence of ventralizing molecules. The LMX1A-expressing progenitors gave rise to grafts containing roof plate-derived choroid plexus cysts as well as ectopically induced TH-positive neurons of a forebrain identity. Early activation of LMX1A prior to floor plate specification was necessary for the dorsalizing effect. Our work suggests using caution in employing LMX1A for the induction of DA fate, as this factor may generate roof plate rather than midbrain fates.

By the author/editor: Rifes, Pedro; Kajtez, Janko; Christiansen, Jo ...; Schörling, Alrik; Rathore, Gaurav ...; Wolf, Daniel A.; show more...; Heuer, Andreas; Kirkeby, Agnete; show less...

About the subject

MEDICAL AND HEALTH SCIENCES: MEDICAL AND HEAL ...; and Basic Medicine; and Neurosciences

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