En1 and Wnt signaling in midbrain dopaminergic neuronal development

Abstract

Dopaminergic neurons of the ventral mesodiencephalon are affected in significant health disorders such as Parkinson's disease, schizophrenia, and addiction. The ultimate goal of current research endeavors is to improve the clinical treatment of such disorders, such as providing a protocol for cell replacement therapy in Parkinson's disease that will successfully promote the specific differentiation of a stem cell into a dopaminergic neuronal phenotype. Decades of research on the developmental mechanisms of the mesodiencephalic dopaminergic (mdDA) system have led to the identification of many signaling pathways and transcription factors critical in its development. The unraveling of these pathways will help fill in the pieces of the puzzle that today dominates neurodevelopment research: how to make and maintain a mdDA neuron. In the present review, we provide an overview of the mdDA system, the processes and signaling molecules involved in its genesis, with a focus on the transcription factor En1 and the canonical Wnt pathway, highlighting recent findings on their relevance - and interplay - in the development and maintenance of the mdDA system.

Neurodevelopmental Perspectives on Wnt Signaling in Psychiatry

“…Conditional deletion of β-catenin mimics these defects [85,86], LRP6 mutants partially mimic the Wnt1 mutant phenotype [57], and Fzd3/Fzd6 double mutants also display disruptions in midbrain development [87]. Moreover, several studies, including LRP6 mutant analysis, overexpression of β-catenin, and ablation of β-catenin support a requirement for Wnt/β-catenin signaling in neurogenesis of midbrain dopaminergic neurons in the mouse [88,89,90,91]. …”

A novel floor plate boundary defined by adjacentEn1andDbx1microdomains distinguishes midbrain dopamine and hypothalamic neurons

“…Engrailed 1 (En1) is known to be expressed in the midbrain beginning at about embryonic day (E) 8.0 (Chi et al, 2003;Davis and Joyner, 1988) and encompasses the majority of the DA primordium, excluding a small number of Th + neurons at the rostral-most extent (Lahti et al, 2012). Engrailed 1 and 2 (En1/2) are important for DA neuron generation and survival (Alberi et al, 2004;Alvarez-Fischer et al, 2011;Alves dos Santos and Smidt, 2011;Ellisor et al, 2012;Nordström et al, 2015;Rekaik et al, 2015;Simon et al, 2001;Veenvliet et al, 2013). Moreover, engrailed proteins are involved in various boundary formation systems such as the diencephalic-dorsal midbrain boundary (Matsunaga et al, 2000;Scholpp et al, 2003) and a D-V boundary in the limb apical ectodermal ridge (Kimmel et al, 2000).…”

Stem Cells-Based Therapeutics for Parkinson’s Disease - A Transcriptomic Analyses During Dopaminergic Neuron Differentiation under 3- and 2- Dimensional Environments using Human Embryonic Stem Cells

“…It was noticed that some known and required pathways for induction and formation of DA neurons were activated in 3D, including Wnt, SHH, MAPK and PD pathways. Wnt signalling pathway has been reported widely to control diverse processes such as cell proliferation, selfrenewal, cell polarity, cell death and cell fate specification [13]. The data has shown significant up-regulation of Wnt signaling genes in 3D such as WNT7B, WNT7A and FZD3.…”

“…The data has shown significant up-regulation of Wnt signaling genes in 3D such as WNT7B, WNT7A and FZD3. WNT7B and WNT7A have been shown to be involved in several developmental processes, including regulation of cell fate and patterning during embryogenesis [13][14][15]. The gene FZD3 has previously been reported that mutant mice with defects in frizzled family receptors such as FZD3 showed a severe impairment of midbrain morphogenesis [13,16].…”