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Review
. 2024 Apr 21;13(8):721.
doi: 10.3390/cells13080721.

Drosophila Contributions towards Understanding Neurofibromatosis 1

Kalliopi Atsoniou  1   2 , Eleni Giannopoulou  1 , Eirini-Maria Georganta  1 , Efthimios M C Skoulakis  1
Affiliations
Review

Drosophila Contributions towards Understanding Neurofibromatosis 1

Kalliopi Atsoniou et al. Cells. .

Abstract

Neurofibromatosis 1 (NF1) is a multisymptomatic disorder with highly variable presentations, which include short stature, susceptibility to formation of the characteristic benign tumors known as neurofibromas, intense freckling and skin discoloration, and cognitive deficits, which characterize most children with the condition. Attention deficits and Autism Spectrum manifestations augment the compromised learning presented by most patients, leading to behavioral problems and school failure, while fragmented sleep contributes to chronic fatigue and poor quality of life. Neurofibromin (Nf1) is present ubiquitously during human development and postnatally in most neuronal, oligodendrocyte, and Schwann cells. Evidence largely from animal models including Drosophila suggests that the symptomatic variability may reflect distinct cell-type-specific functions of the protein, which emerge upon its loss, or mutations affecting the different functional domains of the protein. This review summarizes the contributions of Drosophila in modeling multiple NF1 manifestations, addressing hypotheses regarding the cell-type-specific functions of the protein and exploring the molecular pathways affected upon loss of the highly conserved fly homolog dNf1. Collectively, work in this model not only has efficiently and expediently modelled multiple aspects of the condition and increased understanding of its behavioral manifestations, but also has led to pharmaceutical strategies towards their amelioration.

Keywords: Drosophila; Neurofibromatosis 1; animal models; behavioral deficits; growth.

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Conflict of interest statement

The authors declare no conflicts of interest.

Figures

Figure 1
Figure 1
A schematic representation of the exons of the full-length transcripts of human and Drosophila Nf1. The alternatively spliced exons are indicated in black. Exons encoding different known domains of Nf1 are indicated in different colors (same color code as in Figure 2)—Gray: CSRD, cysteine/serine-rich domain; Light green: TBD, tubulin-binding domain; Yellow: GRD, GTPase-activating protein (GAP)-related domain; Light blue: Sec14, bipartite lipid-binding module with a Sec14-like domain; Olive green: PH, pleckstrin homology domain; Purple: NLS, nuclear localization signal.
Figure 2
Figure 2
Alignment of the human and Drosophila neurofibromin proteins. The human (bottom line, blue) and Drosophila (Nf1-PB) (top line, red) neurofibromin proteins were aligned using both FlyBase (http://flybase.org/reports/FBgn0015269) and NCBI (https://blast.ncbi.nlm.nih.gov/Blast.cgi) protein BLAST tools. The fly protein is 54% identical and 68% similar to the human protein over its entire length. CSRD, cysteine/serine-rich domain (Dm aa 582-928); TBD, tubulin-binding domain (Dm aa 1133-1241); GRD, GTPase-activating protein (GAP)-related domain (Dm aa 1242-1574); Sec14, bipartite lipid-binding module with a Sec14-like domain (Dm aa 1602-1750); PH, pleckstrin homology domain (Dm aa 1759-1868); NLS, nuclear localization signal (Hs aa 2555-2571, absent in Dm); aa, amino acids.
Figure 2
Figure 2
Alignment of the human and Drosophila neurofibromin proteins. The human (bottom line, blue) and Drosophila (Nf1-PB) (top line, red) neurofibromin proteins were aligned using both FlyBase (http://flybase.org/reports/FBgn0015269) and NCBI (https://blast.ncbi.nlm.nih.gov/Blast.cgi) protein BLAST tools. The fly protein is 54% identical and 68% similar to the human protein over its entire length. CSRD, cysteine/serine-rich domain (Dm aa 582-928); TBD, tubulin-binding domain (Dm aa 1133-1241); GRD, GTPase-activating protein (GAP)-related domain (Dm aa 1242-1574); Sec14, bipartite lipid-binding module with a Sec14-like domain (Dm aa 1602-1750); PH, pleckstrin homology domain (Dm aa 1759-1868); NLS, nuclear localization signal (Hs aa 2555-2571, absent in Dm); aa, amino acids.
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