A Mathematical Model of Granule Cell Generation During Mouse Cerebellum Development

Leffler, Shoshana R.; Legué, Emilie; Aristizábal, Orlando; Joyner, Alexandra L.; Peskin, Charles S.; Turnbull, Daniel H.

doi:10.1007/s11538-016-0163-3

Cited by 11 publications

(18 citation statements)

References 27 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…To assess the effects of Rack1 loss on postnatal GNP proliferation in hGFAP-Cre;Rack1 F/F mutants, we labeled dividing neurons with 5-bromo-2′-deoxyuridine (BrdU) at P7, a peak stage for postnatal GNP proliferation (41). Compared with controls, the EGL of mutant mice contained significantly fewer Pax6 + and BrdU + cells ( Fig.…”

Section: Ablation Of Rack1 In Multipotent Nscs Disrupts Cerebellarmentioning

confidence: 99%

Opposite regulation of Wnt/β-catenin and Shh signaling pathways by Rack1 controls mammalian cerebellar development

Yang

Zhu

Cheng

et al. 2019

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

View full text Add to dashboard Cite

The development of the cerebellum depends on intricate processes of neurogenesis, migration, and differentiation of neural stem cells (NSCs) and progenitor cells. Defective cerebellar development often results in motor dysfunctions and psychiatric disorders. Understanding the molecular mechanisms that underlie the complex development of the cerebellum will facilitate the development of novel treatment options. Here, we report that the receptor for activated C kinase (Rack1), a multifaceted signaling adaptor protein, regulates mammalian cerebellar development in a cell type-specific manner. Selective deletion of Rack1 in mouse NSCs or granule neuron progenitors (GNPs), but not Bergmann glial cells (BGs), causes severe defects in cerebellar morphogenesis, including impaired folia and fissure formation. NSCs and GNPs lacking Rack1 exhibit enhanced Wnt/β-catenin signaling but reduced Sonic hedgehog (Shh) signaling. Simultaneous deletion of β-catenin in NSCs, but not GNPs, significantly rescues theRack1mutant phenotype. Interestingly, Rack1 controls the activation of Shh signaling by regulating the ubiquitylation and stability of histone deacetylase 1 (HDAC1)/HDAC2. Suppression of HDAC1/HDAC2 activity in the developing cerebellum phenocopies theRack1mutant. Together, these results reveal a previously unknown role of Rack1 in controlling mammalian cerebellar development by opposite regulation of Wnt/β-catenin and Shh signaling pathways.

show abstract

Section: Ablation Of Rack1 In Multipotent Nscs Disrupts Cerebellarmentioning

confidence: 99%

Opposite regulation of Wnt/β-catenin and Shh signaling pathways by Rack1 controls mammalian cerebellar development

Yang

Zhu

Cheng

et al. 2019

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

View full text Add to dashboard Cite

show abstract

“…The importance of distinguishing the different types of cells which derive from one another has also been established in other contexts (see for instance [17] for the germinative compartment of the epidermis and [18] for the cerebellum).…”

Section: Introductionmentioning

confidence: 97%

A multiscale mathematical model of cell dynamics during neurogenesis in the mouse cerebral cortex

et al. 2019

View full text Add to dashboard Cite

Background Neurogenesis in the murine cerebral cortex involves the coordinated divisions of two main types of progenitor cells, whose numbers, division modes and cell cycle durations set up the final neuronal output. To understand the respective roles of these factors in the neurogenesis process, we combine experimental in vivo studies with mathematical modeling and numerical simulations of the dynamics of neural progenitor cells. A special focus is put on the population of intermediate progenitors (IPs), a transit amplifying progenitor type critically involved in the size of the final neuron pool. Results A multiscale formalism describing IP dynamics allows one to track the progression of cells along the subsequent phases of the cell cycle, as well as the temporal evolution of the different cell numbers. Our model takes into account the dividing apical progenitors (AP) engaged into neurogenesis, both neurogenic and proliferative IPs, and the newborn neurons. The transfer rates from one population to another are subject to the mode of division (proliferative, or neurogenic) and may be time-varying. The model outputs are successfully fitted to experimental cell numbers from mouse embryos at different stages of cortical development, taking into account IPs and neurons, in order to adjust the numerical parameters. We provide additional information on cell kinetics, such as the mitotic and S phase indexes, and neurogenic fraction. Conclusions Applying the model to a mouse mutant for Ftm/Rpgrip1l, a gene involved in human ciliopathies with severe brain abnormalities, reveals a shortening of the neurogenic period associated with an increased influx of newborn IPs from apical progenitors at mid-neurogenesis. Our model can be used to study other mouse mutants with cortical neurogenesis defects and can be adapted to study the importance of progenitor dynamics in cortical evolution and human diseases.

show abstract

“…Based on histological observations (Leffler et al. ), morphological analyses (Nowakowska‐Kotas et al. ) and magnetic resonance imaging (MRI) studies (Szulc et al.…”

Section: Introductionmentioning

confidence: 99%

“…Granule cells influence the shape of the cerebellum; they preferentially migrate first to anterior folia and with some delay to the inferior regions of the cerebellum (Altman & Bayer, 1985). In mathematical models of EGL thickness changes during mouse cerebellum development, three factors have been considered: proliferation giving early increases in the volume of the EGL; transition from proliferation to differentiation, which is responsible for slowing the growth; and the migration of the differentiated granule cells, resulting in the gradual disappearance of the EGL (Leffler et al 2016). The complexity of the description of just one cerebellar layer in one lobule shows the level of the challenge faced by attempts at the description of cerebellum development.…”

Section: Introductionmentioning

confidence: 99%

“…The complexity of the description of just one cerebellar layer in one lobule shows the level of the challenge faced by attempts at the description of cerebellum development. Based on histological observations (Leffler et al 2016), morphological analyses (Nowakowska-Kotas et al 2014) and magnetic resonance imaging (MRI) studies (Szulc et al 2015), it has been stated that not only lobes but also lobules have various growth characteristics.…”

Section: Introductionmentioning

confidence: 99%

See 1 more Smart Citation

Mathematical models of human cerebellar development in the fetal period

2018

View full text Add to dashboard Cite

The evaluation of cerebellar growth in the fetal period forms a part of a widely used examination to identify any features of abnormalities in early stages of human development. It is well known that the development of anatomical structures, including the cerebellum, does not always follow a linear model of growth. The aim of the study was to analyse a variety of mathematical models of human cerebellar development in fetal life to determine their adequacy. The study comprised 101 fetuses (48 males and 53 females) between the 15th and 28th weeks of fetal life. The cerebellum was exposed and measurements of the vermis and hemispheres were performed, together with statistical analyses. The mathematical model parameters of fetal growth were assessed for crown-rump length (CRL) increases, transverse cerebellar diameter and ventrodorsal dimensions of the cerebellar vermis in the transverse plane, and rostrocaudal dimensions of the cerebellar vermis and hemispheres in the frontal plane. A variety of mathematical models were applied, including linear and non-linear functions. Taking into consideration the variance between models and measurements, as well as correlation parameters, the exponential and Gompertz models proved to be the most suitable for modelling cerebellar growth in the second and third trimesters of pregnancy. However, the linear model gave a satisfactory approximation of cerebellar growth, especially in older fetuses. The proposed models of fetal cerebellar growth constructed on the basis of anatomical examination and objective mathematical calculations could be useful in the estimation of fetal development.

show abstract

A Mathematical Model of Granule Cell Generation During Mouse Cerebellum Development

Cited by 11 publications

References 27 publications

Opposite regulation of Wnt/β-catenin and Shh signaling pathways by Rack1 controls mammalian cerebellar development

Opposite regulation of Wnt/β-catenin and Shh signaling pathways by Rack1 controls mammalian cerebellar development

A multiscale mathematical model of cell dynamics during neurogenesis in the mouse cerebral cortex

Mathematical models of human cerebellar development in the fetal period

Contact Info

Product

Resources

About