{{short description|Family of Notch signalling genes}} {{Use dmy dates|date=September 2025}} {{infobox gene}} '''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.<ref name="Fiddes2018">{{cite journal | vauthors = Fiddes IT, Lodewijk GA, Mooring M, Bosworth CM, Ewing AD, Mantalas GL, Novak AM, van den Bout A, Bishara A, Rosenkrantz JL, Lorig-Roach R, Field AR, Haeussler M, Russo L, Bhaduri A, Nowakowski TJ, Pollen AA, Dougherty ML, Nuttle X, Addor MC, Zwolinski S, Katzman S, Kriegstein A, Eichler EE, Salama SR, Jacobs FM, Haussler D | display-authors = 6 | title = Human-Specific NOTCH2NL Genes Affect Notch Signaling and Cortical Neurogenesis | journal = Cell | volume = 173 | issue = 6 | pages = 1356–1369.e22 | date = May 2018 | pmid = 29856954 | doi = 10.1016/j.cell.2018.03.051 | pmc=5986104}}</ref><ref name="Suzuki2018">{{cite journal | vauthors = 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 | title = Human-Specific NOTCH2NL Genes Expand Cortical Neurogenesis through Delta/Notch Regulation | journal = Cell | volume = 173 | issue = 6 | pages = 1370–1384.e16 | date = May 2018 | pmid = 29856955 | doi = 10.1016/j.cell.2018.03.067 | pmc = 6092419 }}</ref><ref name=eu180531>{{cite web | url = https://www.eurekalert.org/pub_releases/2018-05/cp-mnt052418.php | title = Meet NOTCH2NL, the human-specific genes that may have given us our big brains | work = Eurekalert | date = 31 May 2018 }}</ref><ref name=at180531>{{cite web|url=https://www.theatlantic.com/science/archive/2018/05/a-new-genetic-clue-to-how-our-brains-got-so-big/561602/|work=The Atlantic|title=A New Genetic Clue to How Humans Got Such Big Brains | first = Ed | last = Yong | name-list-style = vanc | date = 31 May 2018}}</ref>
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.<ref name=eu180531/> 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.<ref name=eu180531/> 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.<ref name="Namba2024">{{cite journal |last=Namba |first=Takashi |title=What Makes Us Human: Insights from the Evolution and Development of the Human Neocortex |journal=Annual Review of Cell and Developmental Biology |date=October 2024 |volume=40 |pages=427–452 |doi=10.1146/annurev-cellbio-052122-124834 |url=https://www.annualreviews.org/content/journals/10.1146/annurev-cellbio-052122-124834 |access-date=6 September 2025}}</ref>
== 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.<ref name="Fiddes2018" /><ref name="Suzuki2018" />
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.<ref name="Fiddes2018" /><ref name="Suzuki2018" />
== 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.<ref name="Fiddes2018" />
== 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.<ref name="Fiddes2018" /><ref name="Suzuki2018" /><ref name="Namba2024" />
== 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''.<ref name="Namba2024" />
== 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.<ref name="Fiddes2018" /><ref name="Suzuki2018" />
== References == {{Reflist}}
== External links == * {{OMIM|618023|NOTCH2NLA}} – ''Mendelian Inheritance in Man''
Category:Gene families Category:Population genetics Category:Phylogenetics