Research

How is the brain assembled during embryonic development?

Addressing this question has enormous implications for understanding the basis for neurodevelopmental disorders affecting brain size and function, such as microcephaly, intellectual disability, and autism. I focused my research work on investigating genetic and cell biological mechanisms underlying cerebral cortex development, disease and evolution. My major focus is towards understanding genome regulatory layers which control both cell fate and cell signaling in neuroprogenitors across species.

Section of mouse brain at embryonic day 16.5 (E16.5).

Green and Red: plasmid delivered by In utero electroporation (IUE)

Magenta: SOX2 staining

Epigenetic stability in Drosophila dividing neuroblast

Drosophila melanogaster karyotype. Left: female wild type. Right: pendolino deficient individual presenting multiple telomeric fusions creating chromosomal "trains"

The common fruit fly (Drosophila melanogaster) genome has >60% identity overlap with the human species. The small size and ease of genetic manipulation have put this model system the position of contributing some of the greatest scientific discoveries for decades (Thomas Morgan won the Nobel prize for his studies on Drosophila in 1933).

Drosophila telomeres are comprised of DNA sequences that differ dramatically from those of other eukaryotes. Telomere functions, however, are similar to those found in telomerase-based telomeres, even though the underlying mechanisms may differ. Drosophila telomeres use arrays of retrotransposons to maintain chromosome length, while nearly all other eukaryotes rely on telomerase-generated short repeats. Regardless of the DNA sequence, several end-binding proteins are evolutionarily conserved. One of this conserved proteins (Pendolino, or peo) is a U2-Ubiquitin ligase involved in ubiquitination of histon H1. Los-of-function of this protein in neuroblast leads to dramatic telomeric fusions creating chromosomal "trains" and a severe microcephaly in the affected individuals.

Human Brain Evolution

We use a multidisciplinary approach (including evolutionary genomics, mouse genetics and embryology) to uncover the genetic changes that underlie human-specific brain development and function. Specifically we are focused on noncoding regulatory sequences called enhancers. We have identified several enhancers which have acquired rapid changes along the human lineage, and are active in the developing brain. Using transient transgenic assays in mice and iPSCs, we study the activity differences and functional impact of these enhancers upon brain development and behavior. We collaborate with Dr. Greg Wray, an evolutionary genomicist.

The human cortex is 2-3 times bigger than chimpanzee with more complicated neural progenitors which generate a larger number of neurons. However, the protein-coding genes of human and chimpanzee are 99.1% similar. Non-coding regions in the human genome are posited to underlie human brain divergence. Human Accelerated Regions (HARs) are genomic loci, mostly located in non-coding regions, which are rapidly changing in humans but ultra-conserved across other species. Recent studies demonstrated that of the over 3100 HARs in the human genome, almost 50% function as enhancers in neural cells, with target genes related to human fetal brain development. I investigate pivotal role of HARs in human brain evolution, how they regulates target genes and their species-specific mechanisms of action.

DDX3X syndrome

MRI images from neurotypical (red square) and DDX3X patients brains. Red arrows temporal horns. Blue arrowscorpus callosum. yellow arrows anterior commissure

Lennox, Hoye, at al., Neuron 2020

How do de novo mutations in RNA binding proteins disrupt neurodevelopment? We have been studying how an RNA binding protein called DDX3X influences brain development. De novo mutations in DDX3X underlie 1-3% of female intellectual disabilities and are linked to brain malformations including callosal agenesis. We are collaborating with Dr. Elliott Sherr, a human geneticist at UCSF, and Stephen Floor, an RNA biologist at UCSF, to understand how DDX3X missense and nonsense mutations affect cortical development and RNA metabolism. Depletion of DDX3X impairs neuron number by disrupting progenitors. Interestingly, missense mutations in DDX3X cause abnormal RNA-protein granule formation in progenitors. We delivered the missense mutant protein an in vitro model and perform live imaging analysis to attest differences in cell fate during neurodevelopment.

proliferative.avi

Proliferative division

Neuroprogenitor divides and produce two new progenitors

Neurogenic.avi

Neurogenic division

Neuroprogenitor divides and produce two new neurons (orange cells = neurons)

Publications

In revision:

Luo Y, Mangan RJ, Weaver S, Zhao SA, Mosti F, Thomas MC, Karra R, Silver DL, Kellis M, Lowe CB. Intraspecific sequence variation and complete genomes refine the identification of rapidly evolved regions in humans. bioRxiv [Preprint]. 2025 Oct 21:2025.10.20.683446. doi: 10.1101/2025.10.20.683446. PMID: 41279559; PMCID: PMC12633414. In review

Published articles:

Mosti F, Liu J, Lam K, Skavicus S, Kapps VA, Gjoni K, Heaton NS, Pollard KS, Silver DL. Species- specific chromatin architecture and neurogenesis mediated by a human enhancer. bioRxiv [Preprint]. 2025 Aug 8:2025.08.08.669395. doi: 10.1101/2025.08.08.669395. PMID: 41357990; PMCID: PMC12677231. In press at Cell Stem Cell

Liu J, Mosti F, Zhao HT, Lollis D, Sotelo-Fonseca JE, Escobar-Tomlienovich CF, Musso CM, Mao Y, Massri AJ, Doll HM, Moss ND, Sousa AMM, Wray GA, Schmidt ERE, Silver DL. A human specific enhancer fine-tunes radial glia potency and corticogenesis. Nature. 2025 Jul;643(8074):1321-1332. doi: 10.1038/s41586-025-09002-1. Epub 2025 May 14. PMID: 40369080; PMCID: PMC12385787.

Mosti F, Hoye ML, Escobar-Tomlienovich CF, Silver DL. Multi-modal investigation reveals pathogenic features of diverse DDX3X missense mutations. PLoS Genet. 2025 Jan 21;21(1):e1011555. doi: 10.1371/journal.pgen.1011555. PMID: 39836689; PMCID: PMC11771946.

Alsina FC, Lupan BM, Lin LJ, Musso CM, Mosti F, Newman CR, Wood LM, Suzuki A, Agostino M, Moore JK, Silver DL. The RNA-binding protein EIF4A3 promotes axon development by direct control of the cytoskeleton. Cell Rep. 2024 Sep 24;43(9):114666. doi: 10.1016/j.celrep.2024.114666. Epub 2024 Aug 24. PMID: 39182224; PMCID: PMC11488691.

Mangan RJ, Alsina FCǂ, Mosti Fǂ, Sotelo-Fonseca JE, Snellings DA, Au EH, Carvalho J, Sathyan L, Johnson GD, Reddy TE, Silver DL, Lowe CB. Adaptive sequence divergence forged new neurodevelopmental enhancers in humans. Cell. 2022 Nov 23;185(24):4587-4603.e23. doi: 10.1016/j.cell.2022.10.016. PMID: 3642358.

ǂ These authors contribute equally. - Featured on Journal cover

Coni S, Falconio FA, Marzullo M, Munafò M, Zuliani B, Mosti F, Fatica A, Ianniello Z, Bordone R, Macone A, Agostinelli E, Perna A, Matkovic T, Sigrist S, Silvestri G, Canettieri G, Ciapponi L. Translational control of polyamine metabolism by CNBP is required for Drosophila locomotor function. Elife. 2021 Sep 14;10:e69269. doi: 10.7554/eLife.69269. PMID: 34517941; PMCID: PMC8439652

Reviews, Book Chapters:

Mosti F, Silver DL, 4.06 - Genomic basis of human-specific brain features, Editor(s): Jon H. Kaas, Suzana Herculano-Houzel, Evolution of Nervous Systems (Third Edition), Academic Press, 2026, Pages 75-97, ISBN 9780443273810, doi.org/10.1016/B978-0-443-27380-3.00062-2, Copyright Elsevier (2026)

Mosti F, Kawasaki H, Babbit C, di Benedetto B, Silver DL, Kalebic N, Falcone C. Shaping the Neocortex: Radial Glia and Astrocytes in Development and Evolution. J Neurosci. 2025 Nov 12;45(46):e1301252025. doi: 10.1523/JNEUROSCI.1301-25.2025. PMID: 41224664; PMCID: PMC12614052.

Mosti F, Silver DL. Uncovering the HARbingers of human brain evolution. Neuron. 2021 Oct 20;109(20):3231-3233. doi: 10.1016/j.neuron.2021.09.022. PMID: 34672980. Preview.

Liu J, Mosti F, Silver DL. Human brain evolution: Emerging roles for regulatory DNA and RNA. Curr Opin Neurobiol. 2021 Dec;71:170-177. doi: 10.1016/j.conb.2021.11.005. PMID: 34861533. Review

Cover image: Human brain organoids Day60. Green: SOX2, Red:TBR2, Magenta:PH3

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