Engrailed genes are cell-autonomously required to prevent apoptosis in mesencephalic dopaminergic neurons

Abstract

The neuropathological hallmark of Parkinson’s disease is the loss of dopaminergic neurons in the substantia nigra pars compacta, presumably mediated by apoptosis. The homeobox transcription factors engrailed 1 and engrailed 2 are expressed by this neuronal population from early in development to adulthood. Despite a large mid-hindbrain deletion in double mutants null for both genes, mesencephalic dopaminergic (mDA) neurons are induced, become postmitotic and acquire their neurotransmitter phenotype. However, at birth, no mDA neurons are left. We show that the entire population of these neurons is lost by E14 in the mutant animals, earlier than in any other described genetic model system for Parkinson’s disease. This disappearance is caused by apoptosis revealed by the presence of activated caspase 3 in the dying tyrosine hydroxylase-positive mutant cells. Furthermore, using in vitro cell mixing experiments and RNA interference on primary cell culture of ventral midbrain we were able to show that the demise of mDA neurons in the mutant mice is due to a cell-autonomously requirement of the engrailed genes and not a result of the missing mid-hindbrain tissue. Gene silencing in the postmitotic neurons by RNA interference activates caspase 3 and induces apoptosis in less than 24 hours. This rapid induction of cell death in mDA neurons suggests that the engrailed genes participate directly in the regulation of apoptosis, a proposed mechanism for Parkinson’s disease.

Trolox and 17β-Estradiol Protect against Amyloid β-Peptide Neurotoxicity by a Mechanism That Involves Modulation of the Wnt Signaling Pathway

“…This is an interesting observation because the typical neuroprotective action of Trolox is via an antioxidant mechanism (61). Moreover, expression of en-1 (a target gene of the Wnt pathway) is required to prevent apoptosis in mesencephalic dopaminergic neurons, an event that supports the role of the Wnt pathway in neuroprotection (62). These observations could be related to an alternative protective mechanism for neurons, in which both E 2 and Trolox can modulate Wnt ligand genes and Wnt target genes in hippocampal neurons exposed to A␤.…”

Advances in behavioral genetics: mouse models of autism

“…For example, deletion of both Engrailed-1 and Engrailed-2 leads to a striking reduction in serotonergic neurons of the dorsal raphe nucleus, and an overt loss of the noradrenergic neurons of the locus coeruleus. 295 These abnormalities are not evident in the single-null mice, suggesting that redundancy of function between genes could conceal critical roles in neurodevelopment (see also Sgado et al 296 and Alberi et al 297 ). Similarly, mice null for both Fmr1 and Fxr2 (which encodes another fragile X-related protein) show greater behavioral alterations for some, but not all, measures of function, in comparison to the single-null mice.…”

“…9,11,138 Similar to the HOX genes, EN2 encodes a transcription factor important for neurodevelopment, with a critical role in the formation of specific serotonergic and noradrenergic mid-and hindbrain nuclei, 295 and in the survival of specific dopaminergic subpopulations. [296][297][298] En2 deletion animals have behavioral and neuroanatomical abnormalities that reflect alterations in autism. 15,299 For example, both juvenile and adult En2-null mice show deficits in social interaction.…”

Cooperative transcription activation by Nurr1 and Pitx3 induces embryonic stem cell maturation to the midbrain dopamine neuron phenotype

“…Expression analyses and loss-of-function knockout mouse studies have revealed roles for additional transcription factors in the specification and maturation of midbrain DA neurons, including the homeodomain proteins Lmx1b (5), Pitx3 (6)(7)(8)(9), and En1 (10,11). None of these factors are uniquely expressed in midbrain DA neurons, nor are they required for TH expression.…”