Slow progressive degeneration of nigral dopaminergic neurons in postnatal Engrailed mutant mice

Abstract

The homeobox transcription factors Engrailed-1 and Engrailed-2 are required for the survival of mesencephalic dopaminergic neurons in a cell-autonomous and gene-dose-dependent manner. Because of this requirement, the cells die by apoptosis when all four alleles of the Engrailed genes are genetically ablated (En1؊͞؊; En2؊͞؊). In the present study, we show that viable and fertile mice, heterozygous null for Engrailed-1 and homozygous null for Engrailed-2 (En1؉͞؊;En2؊͞؊), have an adult phenotype that resembles key pathological features of Parkinson's disease. Specifically, postnatal mutant mice exhibit a progressive degeneration of dopaminergic neurons in the substantia nigra during the first 3 mo of their lives, leading to diminished storage and release of dopamine in the caudate putamen, motor deficits similar to akinesia and bradykinesia, and a lower body weight. This genetic model may provide access to the molecular etiology for Parkinson's disease and could assist in the development of novel treatments for this neurodegenerative disorder.dopamine ͉ midbrain ͉ mouse mutant ͉ neurodegenerative disease ͉ substantia nigra M esencephalic dopaminergic (mesDA) neurons are the main source of dopamine in the mammalian central nervous system (1). They are located in three distinct nuclei, the substantia nigra pars compacta (SN), the ventral tegmentum (VTA), and the retrorubral field (RRF). Their main innervation targets are the basal ganglia, where they play a major role in controlling emotion, motivation, and motor behavior (2, 3), recognized by their involvement in schizophrenia, addiction, and most prominently in Parkinson's disease (PD; ref. 4). PD is a multisystemic degenerative disorder of the central and peripheral nervous systems. Its hallmark is the progressive degeneration of DA neurons in the SN. The clinical symptoms are resting tremor; muscular rigidity; postural instability; hyposomia; a positive response to the application of L-3,4-dihydroxyphenylalanine (L-DOPA); and the presence of cytoplasmatic inclusions (Lewy bodies) in postmortem brains (5). Additionally, PD patients are often characterized by weight loss starting before diagnosis and continuing with disease progression (6, 7).The homeodomain transcription factors Engrailed-1 and -2 (En1 and En2) are expressed by all mesDA neurons soon after differentiation and then continuously into adulthood. They are cell-autonomously and in a gene-dose-dependent manner required for the survival of this neuronal population, leading to the complete loss of the cells in mutant mice homozygous null for both genes (En1Ϫ͞Ϫ;En2Ϫ͞Ϫ; refs. 8 and 9). In their function as survival factors for mesDA neurons, the two genes are redundant and can compensate for each other (9, 10). The single-null mutants for either En1 (En1Ϫ͞Ϫ) or En2 (En2Ϫ͞Ϫ) show no significant alterations in the organization of the mesDA system at birth, but the mice with genotypes intermediate to the single and double mutants are distinctively different from each other. Whereas En1Ϫ͞Ϫ;En2ϩ͞Ϫ mice die at po...

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.…”

Human midbrain precursors activate the expected developmental genetic program and differentiate long-term to functional A9 dopamine neurons in vitro. Enhancement by Bcl-XL

“…Recent studies have proposed a maintenance and survival role for some of the factors studied here (EN1, LMX1B, NURR1 and PITX3), in addition to their known developmental roles [49][50][51][52][53][54][55] (reviewed in [6,15,49]). We therefore analyzed their expression in 30d-differentiated control and Bcl-X L hVMl cells.…”

“…Bcl-X L effects on maturation are marginal, as discussed later. EN1, LMX1B, NURR1 and PITX3 are not only involved in development, but also in the survival/maintenance of functional A9-DAn ( [50][51][52][53][54] reviewed in [6,15,24,49,77]). In control hVMl cells the expression levels of these genes first increase during differentiation (but for PITX3), to later return to values close to basal levels ( Fig.…”

Spatiotemporally separable Shh domains in the midbrain define distinct dopaminergic progenitor pools

“…In addition to the anatomical and functional differences, transcriptome as well as marker analyses of neurons in mDA clusters have also revealed some molecular differences (2)(3)(4)(5). Finally, neurons in the SNpc are selectively lost in Parkinson's disease (PD) patients (6,7), as well as in various genetic mouse models (8)(9)(10)(11), further highlighting the physiological diversity of mDA. However, little is known about whether mDA diversity is encoded at the progenitor cell level.…”