NOTCH2NL

NOTCH2NLA
Identifiers
Aliases	NOTCH2NLA , N2N, notch 2 N-terminal like, notch 2 N-terminal like A, NOTCH2NL
External IDs	OMIM: 618023; HomoloGene: 89329; GeneCards: NOTCH2NLA; OMA:NOTCH2NLA - orthologs
Gene location (Human) Chr. Chromosome 1 (human) [1] Band 1q21.1 Start 146,146,203 bp [1] End 146,229,041 bp [1]
RNA expression pattern Bgee Human Mouse (ortholog) Top expressed in corpus callosum Achilles tendon sural nerve monocyte bone marrow cell epithelium of colon stromal cell of endometrium zone of skin skin of abdomen skin of leg n/a More reference expression data BioGPS n/a
Gene ontology Molecular function calcium ion binding protein binding Notch binding Cellular component cytoplasm extracellular region plasma membrane Biological process Notch signaling pathway multicellular organism development cell differentiation cerebral cortex development positive regulation of Notch signaling pathway Sources:Amigo / QuickGO
Orthologs Species Human Mouse Entrez 388677 n/a Ensembl ENSG00000264343 n/a UniProt Q7Z3S9 P0DPK4 n/a RefSeq (mRNA) NM_203458 NM_001364006 NM_001395231 NM_001395232 n/a RefSeq (protein) NP_001350936 NP_001350937 NP_001350935 NP_982283 n/a Location (UCSC) Chr 1: 146.15 – 146.23 Mb n/a PubMed search [2] n/a
Wikidata
View/Edit Human

Notch homolog 2 N-terminal-like is a family of proteins that in humans consists of 3 proteins (NOTCH2NLA, NOTCH2NLB, and NOTCH2NLC) and is encoded by NOTCH2NL gene. It appears to play a key role in the development of the prefrontal cortex, a part of the brain. ^{[3] [4] [5] [6]}

NOTCH2NL increases the number of cortical stem cells, which while delaying the generation of neurons ultimately leads to a greater number of neurons and larger brains. ^[5] NOTCH2NL copy number loss and gain is associated with various neurological disorders, and they showed that loss of NOTCH2NL in cortical organoids leads to the organoids being smaller, while resulting in premature differentiation of cortical stem cells into neurons. ^[5] The role of NOTCH2NL in the development of the human brain together with the evolutionary history of NOTCH2NL genes, suggests that the emergence of NOTCH2NL genes may have contributed to the increase in size of the human neocortex which tripled over the last two million years. ^[7]

Structure and function

Proteins encoded by NOTCH2NL act as regulators of Notch signaling, a cell–cell communication mechanism that controls differentiation, proliferation, and cell death. NOTCH2NL is notably expressed in cortical stem/progenitor cells and influences their division and maturation during brain development, helping to maintain progenitor activity and regulate neurogenesis in the human neocortex. ^{[3] [4]}

NOTCH2NL genes increase the number of cortical stem cells by prolonging their undifferentiated divisions; although this delays neuron production, it ultimately yields more neurons and contributes to larger brain size. Copy-number loss or gain of NOTCH2NL has been associated with neurodevelopmental phenotypes, and loss of NOTCH2NL in human cortical organoids reduces organoid size and induces premature differentiation of cortical stem cells into neurons. ^{[3] [4]}

Human specificity

The NOTCH2NL gene family is specific to humans while related sequences are present in some other primates. Comparative genomic analyses indicate that NOTCH2NL arose from a partial duplication of NOTCH2 in the great-ape lineage; functional copies are found in humans, whereas non-human great apes harbor related pseudogene-like sequences. ^[3]

Role in brain development

NOTCH2NL has been implicated in the development of the prefrontal cortex, a region associated with higher cognitive functions such as working memory and decision-making. By expanding and maintaining the pool of cortical progenitors, NOTCH2NL increases neuronal output during development. ^{[3] [4] [7]}

Evolutionary implications

The appearance of NOTCH2NL in human evolution has been discussed in relation to neocortical expansion and growing cognitive complexity. Comparative and evolutionary studies, including ancient DNA comparisons (e.g., Neanderthals and Denisovans), explore variants in this locus and their possible contributions to the increased brain size of Homo sapiens . ^[7]

Dysfunction and neurological disorders

Altered copy number of NOTCH2NL has been associated with neurodevelopmental conditions. Experimental studies in human cellular models report that NOTCH2NL loss reduces the size of cortical organoids and triggers premature differentiation of cortical stem cells into neurons. ^{[3] [4]}

References

1. GRCh38: Ensembl release 89: ENSG00000264343 – Ensembl, May 2017
2. "Human PubMed Reference:". National Center for Biotechnology Information, U.S. National Library of Medicine.
3. Fiddes IT, Lodewijk GA, Mooring M, Bosworth CM, Ewing AD, Mantalas GL, et al. (May 2018). "Human-Specific NOTCH2NL Genes Affect Notch Signaling and Cortical Neurogenesis". Cell. 173 (6): 1356–1369.e22. doi:10.1016/j.cell.2018.03.051. PMC   5986104 . PMID   29856954.
4. Suzuki IK, Gacquer D, Van Heurck R, Kumar D, Wojno M, Bilheu A, Herpoel A, Lambert N, Cheron J, Polleux F, Detours V, Vanderhaeghen P (May 2018). "Human-Specific NOTCH2NL Genes Expand Cortical Neurogenesis through Delta/Notch Regulation". Cell. 173 (6): 1370–1384.e16. doi:10.1016/j.cell.2018.03.067. PMC   6092419 . PMID   29856955.
5. "Meet NOTCH2NL, the human-specific genes that may have given us our big brains". Eurekalert. 31 May 2018.
6. Yong E (31 May 2018). "A New Genetic Clue to How Humans Got Such Big Brains". The Atlantic.
7. Namba, Takashi (October 2024). "What Makes Us Human: Insights from the Evolution and Development of the Human Neocortex". Annual Review of Cell and Developmental Biology. 40: 427–452. doi:10.1146/annurev-cellbio-052122-124834 . Retrieved 6 September 2025.

External links

• Online Mendelian Inheritance in Man (OMIM): NOTCH2NLA - 618023 – Mendelian Inheritance in Man