Programmed Cell Death Recruits Macrophages Into the Developing Mouse Cochlea

Programmed cell death (PCD) plays a critical role in the development and maturation of the cochlea. Significant remodeling occurs among cells of the greater epithelial ridge (GER) of Kölliker’s organ, leading to tissue regression and formation of the inner sulcus. In mice, this event normally occurs between postnatal days 5–15 (P5-15) and is regulated by thyroid hormone (T3). During this developmental time period, the cochlea also contains a large population of macrophages. Macrophages are frequently involved in the phagocytic clearance of dead cells, both during development and after injury, but the role of macrophages in the developing cochlea is unknown. This study examined the link between developmental cell death in the GER and the recruitment of macrophages into this region. Cell death in the basal GER begins at P5 and enhanced numbers of macrophages were observed at P7. This pattern of macrophage recruitment was unchanged in mice that were genetically deficient for CX3CR1, the receptor for fractalkine (a known macrophage chemoattractant). We found that injection of T3 at P0 and P1 caused GER cell death to begin at P3, and this premature PCD was accompanied by earlier recruitment of macrophages. We further found that depletion of macrophages from the developing cochlea (using CX3CR1DTR/+ mice and treatment with the CSF1R antagonist BLZ945) had no effect on the pattern of GER regression. Together, these findings suggest that macrophages are recruited into the GER region after initiation of developmental PCD, but that they are not essential for GER regression during cochlear remodeling.

Developmental cell death of cortical projection neurons is controlled by a Bcl11a/Bcl6-dependent pathway

Developmental neuron death plays a pivotal role in refining organization and wiring during neocortex formation. Aberrant regulation of this process results in neurodevelopmental disorders including impaired learning and memory. Underlying molecular pathways are incompletely determined. Loss of Bcl11a in cortical projection neurons induces pronounced cell death in upper-layer cortical projection neurons during postnatal corticogenesis. We used this genetic model to explore genetic mechanisms by which developmental neuron death is controlled. Unexpectedly, we found Bcl6, previously shown to be involved in transition of cortical neurons from progenitor to postmitotic differentiation state to provide a major check point regulating neuron survival during late cortical development. We show that Bcl11a is a direct transcriptional regulator of Bcl6. Deletion of Bcl6 exerts death of cortical projection neurons. In turn, reintroduction of Bcl6 into Bcl11a mutants prevents induction of cell death in these neurons. Together, our data identify a novel Bcl11a/Bcl6-dependent molecular pathway in regulation of developmental cell death during corticogenesis.

BLMP-1 promotes developmental cell death in C. elegans by timely repression of ced-9/bcl-2 transcription

Programmed cell death (PCD) is a common cell fate in metazoan development. PCD effectors are extensively studied, but how they are temporally regulated is less understood. Here we report a mechanism controlling tail-spike cell death onset during C. elegans development. We show that the Zn-finger transcription factor BLMP-1/Blimp1, which controls larval development timing, also regulates embryonic tail-spike cell death initiation. BLMP-1 functions upstream of CED-9/BCL-2 and in parallel to DRE-1/FBXO11, another CED-9 and tail-spike cell death regulator. BLMP-1 expression is detected in the tail-spike cell shortly after the cell is born, and blmp-1 mutations promote ced-9-dependent tail-spike cell survival. BLMP-1 binds ced-9/bcl-2 gene regulatory sequences, and inhibits ced-9 transcription just before cell-death onset. BLMP-1 and DRE-1 function together to regulate developmental timing, and their mammalian homologs regulate B-lymphocyte fate. Our results, therefore, identify roles for developmental timing genes in cell-death initiation, and suggest conservation of these functions.

Programmed cell death recruits macrophages into the developing mouse cochlea

Programmed cell death (PCD) plays a critical role in the development and maturation of the cochlea. Significant remodeling occurs among cells of the greater epithelial ridge (GER) of Kölliker’s organ, leading to tissue regression and formation of the inner sulcus. In mice, this event normally occurs between postnatal days 5-15 (P5-15) and is regulated by thyroid hormone (T3). During this developmental time period, the cochlea also contains a large population of macrophages. Macrophages are frequently involved in the phagocytic clearance of dead cells, both during development and after injury, but the role of macrophages in the developing cochlea is unknown. This study examined the link between developmental cell death in the GER and the recruitment of macrophages into this region. Cell death in the basal GER begins at P5 and enhanced numbers of macrophages were observed at P7. This pattern of macrophage recruitment was unchanged in mice that were genetically deficient for CX3CR1, the receptor for fractalkine (a known macrophage chemoattractant). We found that injection of T3 at P0 and P1 caused GER cell death to begin at P3, and this premature PCD was accompanied by earlier recruitment of macrophages. We further found that depletion of macrophages from the developing cochlea (using CX3CR1DTR/+ mice and treatment with the CSF1R antagonist BLZ945) had no effects on the pattern of GER regression. Together, these findings suggest that macrophages are recruited into the GER region after initiation of developmental PCD, but that they are not essential for GER regression during cochlear remodeling.

Differences in Neuronal Numbers, Morphology and Developmental Apoptosis in Mice Nigra Provide Evidence of Ontogenic Origin of Vulnerability to Parkinson’s Disease

Parkinson’s disease (PD) prevalence varies by ethnicity. In an earlier study we replicated the reduced vulnerability to PD in an admixed population, using 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP)-susceptible C57BL/6J, MPTP-resistant CD-1 and their F1 crossbreds. In the present study we investigated if the differences have a developmental origin. Substantia nigra was evaluated atpostnatal days 2 (P2), P6, P10, P14, P18, and P22. C57BL/6J mice had smaller nigra and fewer dopaminergic neurons than the CD-1 and crossbreds at P2, which persisted through development. A significant increase in numbers and nigral volume was observed across strains till P14. A drastic decline thereafter was specific to C57BL/6J. CD-1 and crossbreds retained their numbers from P14 to stabilize with supernumerary neurons at adulthood. The neuronal size increased gradually to attain adult morphology at P10 in the resistant strains, vis-à-vis at P22 in C57BL/6J. Accordingly, in comparison to C57BL/6J, the nigra of CD-1 and reciprocal crossbreds possessed cyto-morphological features of resilience, since birth. The considerably lesser dopaminergic neuronal loss in the CD-1 and crossbreds seen at P2, P14 and thereafter was complemented by attenuated developmental cell death. The differences in programmed cell death were confirmed by reduced TUNEL labelling, AIF and caspase-3 expression. GDNF expression aligned with the cell death pattern at P2 and P14 in both nigra and striatum. Earlier maturity of nigra and its neurons appear to be better features that reflect as MPTP-resistance at adulthood. Thus variable MPTP-vulnerability in mice and also differential susceptibility to PD in humans may arise early during nigral development.

Differences in neuronal numbers, morphology and developmental apoptosis in mice nigra provide experimental evidence of ontogenic origin of vulnerability to Parkinson’s disease

Parkinson disease (PD) prevalence varies by ethnicity. In an earlier study we replicated the reduced vulnerability to PD in an admixed population, using 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP)-susceptible C57BL/6J, MPTP-resistant CD-1 and their F1 crossbreds. In the present study we investigated if the differences have a developmental origin. Substantia nigra was evaluated at postnatal days 2 (P2), P6, P10, P14, P18, and P22. C57BL/6J mice had smaller nigra and fewer dopaminergic neurons than the CD-1 and crossbreds at P2, which persisted through development. A significant increase in numbers and nigral volume was observed across strains till P14. A drastic decline thereafter was specific to C57BL/6J. CD-1 and crossbreds retained their numbers from P14 to stabilize with supernumerary neurons at adulthood. The neuronal size increased gradually to attain adult morphology at P10 in the resistant strains, vis-à-vis at P22 in C57BL/6J. Accordingly, in comparison to C57BL/6J, the nigra of CD-1 and reciprocal crossbreds possessed cyto-morphological features of resilience, since birth. The considerably lesser dopaminergic neuronal loss in the CD-1 and crossbreds seen at P2, P14 and thereafter was complemented by attenuated developmental cell death. The differences in programmed cell death were confirmed by reduced TUNEL labelling, AIF and caspase-3 expression. GDNF expression aligned with the cell death pattern at P2 and P14 in both nigra and striatum. Earlier maturity of nigra and its neurons appear to be better features that reflect as MPTP-resistance at adulthood. Thus variable MPTP-vulnerability in mice and also differential susceptibility to PD in humans may arise early during nigral development.

Cell death in animal development

ABSTRACTCell death is an important facet of animal development. In some developing tissues, death is the ultimate fate of over 80% of generated cells. Although recent studies have delineated a bewildering number of cell death mechanisms, most have only been observed in pathological contexts, and only a small number drive normal development. This Primer outlines the important roles, different types and molecular players regulating developmental cell death, and discusses recent findings with which the field currently grapples. We also clarify terminology, to distinguish between developmental cell death mechanisms, for which there is evidence for evolutionary selection, and cell death that follows genetic, chemical or physical injury. Finally, we suggest how advances in understanding developmental cell death may provide insights into the molecular basis of developmental abnormalities and pathological cell death in disease.