Programmed Cell Death in Neurodevelopment

Yamaguchi, Yoshifumi; Miura, Masayuki

doi:10.1016/j.devcel.2015.01.019

Cited by 202 publications

(175 citation statements)

References 146 publications

(172 reference statements)

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“…In laminar brain regions, such as the cerebral and cerebellar cortices, neurons perform long distance migration and extend their axons to make highly precise synaptic connections with targets. Genetic mutations, as well as insults of heterogeneous nature, that concern the ability of neural cells to perform these sequenced steps, result in developmental arrest and may lead to death of the affected cells (Yamaguchi and Miura, 2015).…”

Section: Introductionmentioning

confidence: 99%

Cell death and neurodegeneration in the postnatal development of cerebellar vermis in normal and Reeler mice

Castagna

Merighi

2016

Annals of Anatomy - Anatomischer Anzeiger

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Section: Introductionmentioning

confidence: 99%

Cell death and neurodegeneration in the postnatal development of cerebellar vermis in normal and Reeler mice

Castagna

Merighi

2016

Annals of Anatomy - Anatomischer Anzeiger

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“…The same concentration of BGP-15 on control neurons induced a small but significant increase in survival, perhaps resulting from a reduction in naturally occurring programmed cell death (Fig. 4A) (43). We next tested the efficacy of BGP-15 in vivo by injecting pregnant dams once daily from E12.5 to E16.5 with either PBS or 100 mg/kg of BGP-15 i.p.…”

Section: Bgp-15 Normalizes Impaired Actin Dynamics In Ikbkapmentioning

confidence: 99%

BGP-15 prevents the death of neurons in a mouse model of familial dysautonomia

Ohlen

Russell

Brownstein

et al. 2017

Proc. Natl. Acad. Sci. U.S.A.

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Hereditary sensory and autonomic neuropathy type III, or familial dysautonomia [FD; Online Mendelian Inheritance in Man (OMIM) 223900], affects the development and long-term viability of neurons in the peripheral nervous system (PNS) and retina. FD is caused by a point mutation in the gene IKBKAP/ELP1 that results in a tissue-specific reduction of the IKAP/ELP1 protein, a subunit of the Elongator complex. Hallmarks of the disease include vasomotor and cardiovascular instability and diminished pain and temperature sensation caused by reductions in sensory and autonomic neurons. It has been suggested but not demonstrated that mitochondrial function may be abnormal in FD. We previously generated an Ikbkap/Elp1 conditional-knockout mouse model that recapitulates the selective death of sensory (dorsal root ganglia) and autonomic neurons observed in FD. We now show that in these mice neuronal mitochondria have abnormal membrane potentials, produce elevated levels of reactive oxygen species, are fragmented, and do not aggregate normally at axonal branch points. The small hydroxylamine compound BGP-15 improved mitochondrial function, protecting neurons from dying in vitro and in vivo, and promoted cardiac innervation in vivo. Given that impairment of mitochondrial function is a common pathological component of neurodegenerative diseases such as amyotrophic lateral sclerosis and Alzheimer's, Parkinson's, and Huntington's diseases, our findings identify a therapeutic approach that may have efficacy in multiple degenerative conditions.T he autonomic nervous system is essential for homeostasis, and its disruption in familial dysautonomia (FD) can have fatal consequences resulting from cardiovascular instability, respiratory dysfunction, and/or sudden death during sleep (1-3). In addition to developmental decreases in the number of sensory and autonomic neurons, FD patients undergo a progressive loss of peripheral neurons and retinal ganglion cells. The latter loss may ultimately lead to blindness (4, 5). More than 98% of FD cases result from a single base substitution (IVS20+6T > C) in the IKBKAP/ELP1 gene (3, 6). This mutation is carried by 1 in 27 to 1 in 32 Ashkenazi Jews (3, 6). The protein encoded by the IKBKAP/ELP1 gene, IKAP/ELP1, is a scaffolding protein for the six-subunit Elongator complex (ELP1-ELP6), which modifies tRNAs during translation (7). Why reduction in the IKAP/ ELP1 protein results in neuronal death is unknown, and we have sought to elucidate the cellular and molecular mechanisms that cause progressive neurodegeneration in FD to help identify treatments that improve neuronal function and viability.Accumulating evidence indicates that cells from FD patients and from mouse models with deletions in the Elongator subunits Ikbkap/Elp1 or Elp3 experience intracellular stress (4,5,(8)(9)(10) resulting from the direct and/or indirect consequences of impaired translation (7, 11). The C terminus of IKAP/ELP1 has been shown to bind c-Jun N-terminal kinase (JNK) and to regulate JNK cytosolic stress signaling (12)....

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“…Interestingly, this mechanism could explain some of the early phenotypes observed in apoptosis-deficient mice, which were originally attributed to an excessive number of neural cells that fail to die by apoptosis (Kuan et al, 2000). Thus, an intriguing possibility would be that the main function of apoptosis in the central nervous system is not to simply control cell number, as has been generally thought, but to regulate its morphogenesis by modulating morphogen signaling and gradients (Yamaguchi and Miura, 2015).…”

Section: Genital Rotation In Drosophilamentioning

confidence: 99%

Spreading the word: non-autonomous effects of apoptosis during development, regeneration and disease

2015

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Apoptosis, in contrast to other forms of cell death such as necrosis, was originally regarded as a 'silent' mechanism of cell elimination designed to degrade the contents of doomed cells. However, during the past decade it has become clear that apoptotic cells can produce diverse signals that have a profound impact on neighboring cells and tissues. For example, apoptotic cells can release factors that influence the proliferation and survival of adjacent tissues. Apoptosis can also affect tissue movement and morphogenesis by modifying tissue tension in surrounding cells. As we review here, these findings reveal unexpected roles for apoptosis in tissue remodeling during development, as well as in regeneration and cancer.

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Programmed Cell Death in Neurodevelopment

Cited by 202 publications

References 146 publications

Cell death and neurodegeneration in the postnatal development of cerebellar vermis in normal and Reeler mice

Cell death and neurodegeneration in the postnatal development of cerebellar vermis in normal and Reeler mice

BGP-15 prevents the death of neurons in a mouse model of familial dysautonomia

Spreading the word: non-autonomous effects of apoptosis during development, regeneration and disease

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