RRP7A links primary microcephaly to dysfunction of ribosome biogenesis, resorption of primary cilia, and neurogenesis

Farooq, Muhammad; Lindbæk, Louise; Krogh, Nicolai; Doğanlı, Canan; Keller, Charlotte; Mönnich, Maren; Gonçalves, André; Sakthivel, S.; Mang, Yuan; Fatima, Ambrin; Andersen, Vivi Søgaard; Hussain, Muhammad Sajid; Eiberg, Hans; Hansen, Lars; Kjaer, Klaus; Gopalakrishnan, Jay; Pedersen, Lotte B.; Møllgård, Kjeld; Nielsen, Henrik; Baig, Shahid Mahmood; Tommerup, Niels; Christensen, Søren Tvorup; Larsen, Lars Allan

doi:10.1038/s41467-020-19658-0

Cited by 39 publications

(26 citation statements)

References 78 publications

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“…The mechanism for the delay in ciliary resorption upon RRP7A reduction, however, is not yet known. On the other hand, a function of RRP7A in RNA processing and ribosome biogenesis has been shown both in cell culture and in zebrafish embryos ( Farooq et al, 2020 ). Which of these two—quite diverging—processes, ciliary resorption vs. ribosome biogenesis, is responsible for the microcephaly phenotype remains to be elucidated.…”

Section: Primary Cilium Disassembly: License For Mitosismentioning

confidence: 99%

Primary Cilia and Centrosomes in Neocortex Development

Wilsch‐Bräuninger

Huttner

2021

Front. Neurosci.

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During mammalian brain development, neural stem and progenitor cells generate the neurons for the six-layered neocortex. The proliferative capacity of the different types of progenitor cells within the germinal zones of the developing neocortex is a major determinant for the number of neurons generated. Furthermore, the various modes of progenitor cell divisions, for which the orientation of the mitotic spindle of progenitor cells has a pivotal role, are a key parameter to ensure the appropriate size and proper cytoarchitecture of the neocortex. Here, we review the roles of primary cilia and centrosomes of progenitor cells in these processes during neocortical development. We specifically focus on the apical progenitor cells in the ventricular zone. In particular, we address the alternating, dual role of the mother centriole (i) as a component of one of the spindle poles during mitosis, and (ii) as the basal body of the primary cilium in interphase, which is pivotal for the fate of apical progenitor cells and their proliferative capacity. We also discuss the interactions of these organelles with the microtubule and actin cytoskeleton, and with junctional complexes. Centriolar appendages have a specific role in this interaction with the cell cortex and the plasma membrane. Another topic of this review is the specific molecular composition of the ciliary membrane and the membrane vesicle traffic to the primary cilium of apical progenitors, which underlie the ciliary signaling during neocortical development; this signaling itself, however, is not covered in depth here. We also discuss the recently emerging evidence regarding the composition and roles of primary cilia and centrosomes in basal progenitors, a class of progenitors thought to be of particular importance for neocortex expansion in development and evolution. While the tight interplay between primary cilia and centrosomes makes it difficult to allocate independent roles to either organelle, mutations in genes encoding ciliary and/or centrosome proteins indicate that both are necessary for the formation of a properly sized and functioning neocortex during development. Human neocortical malformations, like microcephaly, underpin the importance of primary cilia/centrosome-related processes in neocortical development and provide fundamental insight into the underlying mechanisms involved.

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Section: Primary Cilium Disassembly: License For Mitosismentioning

confidence: 99%

Primary Cilia and Centrosomes in Neocortex Development

Wilsch‐Bräuninger

Huttner

2021

Front. Neurosci.

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“…MCPH-derived dermal fibroblasts display defects in rRNA processing and ciliary dynamics. Rrp7a knockout zebrafish exhibit microcephaly-like phenotypes [120]. Thus, it would be interesting to know whether and how Rrp7a links centrosome dynamics and rRNA biogenesis during cortical development, and whether p53 inactivation is sufficient to revert phenotypes caused by Rrp7a deficiency.…”

Section: Interrelationships Of the Cellular Processes Implicated In P53 Activation-associated Disordersmentioning

confidence: 99%

p53 Activation in Genetic Disorders: Different Routes to the Same Destination

Tsai

Tarn

2021

IJMS

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The tumor suppressor p53 is critical for preventing neoplastic transformation and tumor progression. Inappropriate activation of p53, however, has been observed in a number of human inherited disorders that most often affect development of the brain, craniofacial region, limb skeleton, and hematopoietic system. Genes related to these developmental disorders are essentially involved in transcriptional regulation/chromatin remodeling, rRNA metabolism, DNA damage-repair pathways, telomere maintenance, and centrosome biogenesis. Perturbation of these activities or cellular processes may result in p53 accumulation in cell cultures, animal models, and perhaps humans as well. Mouse models of several p53 activation-associated disorders essentially recapitulate human traits, and inactivation of p53 in these models can alleviate disorder-related phenotypes. In the present review, we focus on how dysfunction of the aforementioned biological processes causes developmental defects via excessive p53 activation. Notably, several disease-related genes exert a pleiotropic effect on those cellular processes, which may modulate the magnitude of p53 activation and establish or disrupt regulatory loops. Finally, we discuss potential therapeutic strategies for genetic disorders associated with p53 misactivation.

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“…Primary non-syndromic microcephaly makes a distinct subclass, termed as microcephaly primary hereditary (MCPH (MIM #251200)) or autosomal recessive primary microcephaly. It is known to be associated with 28 different genes, the latest being RRP7A, which encodes a novel component of ribosome biogenesis and was identified in a large Pakistani family [ 3 , 4 , 5 ]. MCPH has been clinically defined as a disorder of prenatal onset, non-progressive intellectual disability (ID), lack of major brain malformations or major birth defect in a non-central nervous system organ [ 6 ].…”

Section: Introductionmentioning

confidence: 99%

Modifier Genes in Microcephaly: A Report on WDR62, CEP63, RAD50 and PCNT Variants Exacerbating Disease Caused by Biallelic Mutations of ASPM and CENPJ

Makhdoom

Waseem

Iqbal

et al. 2021

Genes

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Congenital microcephaly is the clinical presentation of significantly reduced head circumference at birth. It manifests as both non-syndromic—microcephaly primary hereditary (MCPH)—and syndromic forms and shows considerable inter- and intrafamilial variability. It has been hypothesized that additional genetic variants may be responsible for this variability, but data are sparse. We have conducted deep phenotyping and genotyping of five Pakistani multiplex families with either MCPH (n = 3) or Seckel syndrome (n = 2). In addition to homozygous causal variants in ASPM or CENPJ, we discovered additional heterozygous modifier variants in WDR62, CEP63, RAD50 and PCNT—genes already known to be associated with neurological disorders. MCPH patients carrying an additional heterozygous modifier variant showed more severe phenotypic features. Likewise, the phenotype of Seckel syndrome caused by a novel CENPJ variant was aggravated to microcephalic osteodysplastic primordial dwarfism type II (MOPDII) in conjunction with an additional PCNT variant. We show that the CENPJ missense variant impairs splicing and decreases protein expression. We also observed centrosome amplification errors in patient cells, which were twofold higher in MOPDII as compared to Seckel cells. Taken together, these observations advocate for consideration of additional variants in related genes for their role in modifying the expressivity of the phenotype and need to be considered in genetic counseling and risk assessment.

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RRP7A links primary microcephaly to dysfunction of ribosome biogenesis, resorption of primary cilia, and neurogenesis

Cited by 39 publications

References 78 publications

Primary Cilia and Centrosomes in Neocortex Development

Primary Cilia and Centrosomes in Neocortex Development

p53 Activation in Genetic Disorders: Different Routes to the Same Destination

Modifier Genes in Microcephaly: A Report on WDR62, CEP63, RAD50 and PCNT Variants Exacerbating Disease Caused by Biallelic Mutations of ASPM and CENPJ

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