Nhlh1, a member of the basic helix-loop-helix family of transcription factors, is crucial in neuronal differentiation and development. It is expressed in the developing neural tube, olfactory and vomeronasal sensory neurons, and is involved in pathways such as the Sonic Hedgehog (Shh) pathway [1,2,4,5,6]. Genetic models, especially mouse models, are valuable for studying its functions due to its restricted expression in the nervous system [3].

Null mice lacking Nhlh1 are predisposed to premature, adult-onset, unexpected death, with electrocardiograms showing decreased heart rate variability, stress-induced arrhythmia, and impaired baroreceptor sensitivity, suggesting a role of Nhlh1 in autonomic nervous system regulation of the heart [3]. Also, Nhlh1 mRNA expression is downregulated in ATF5-deficient olfactory organs, indicating it is a target gene of ATF5 and is involved in the differentiation of olfactory and vomeronasal sensory neurons [2].

In conclusion, Nhlh1 plays essential roles in neuronal differentiation, especially in the autonomic nervous system and olfactory system. The study of Nhlh1-deficient mouse models has provided insights into its role in arrhythmia and autonomic dysfunction, highlighting its significance in understanding these disease-related mechanisms [2,3].

References:

1. Mullick, A, Groulx, N, Trasler, D, Gros, P. . Nhlh1, a basic helix-loop-helix transcription factor, is very tightly linked to the mouse looptail (Lp) mutation. In Mammalian genome : official journal of the International Mammalian Genome Society, 6, 700-4. doi:. https://pubmed.ncbi.nlm.nih.gov/8563167/

2. Ishii, Chiharu, Nakano, Haruo, Higashiseto, Riko, Takahashi, Shigeru, Takahashi, Yuji. 2024. Nescient helix-loop-helix 1 (Nhlh1) is a novel activating transcription factor 5 (ATF5) target gene in olfactory and vomeronasal sensory neurons in mice. In Cell and tissue research, 396, 85-94. doi:10.1007/s00441-024-03871-0. https://pubmed.ncbi.nlm.nih.gov/38388750/

3. Cogliati, Tiziana, Good, Deborah J, Haigney, Mark, Koch, Walter J, Kirsch, Ilan R. . Predisposition to arrhythmia and autonomic dysfunction in Nhlh1-deficient mice. In Molecular and cellular biology, 22, 4977-83. doi:. https://pubmed.ncbi.nlm.nih.gov/12077327/

4. Murdoch, J N, Eddleston, J, Leblond-Bourget, N, Stanier, P, Copp, A J. . Sequence and expression analysis of Nhlh1: a basic helix-loop-helix gene implicated in neurogenesis. In Developmental genetics, 24, 165-77. doi:. https://pubmed.ncbi.nlm.nih.gov/10079519/

5. De Smaele, Enrico, Fragomeli, Caterina, Ferretti, Elisabetta, Giannini, Giuseppe, Gulino, Alberto. . An integrated approach identifies Nhlh1 and Insm1 as Sonic Hedgehog-regulated genes in developing cerebellum and medulloblastoma. In Neoplasia (New York, N.Y.), 10, 89-98. doi:. https://pubmed.ncbi.nlm.nih.gov/18231642/

6. Martinez-Lopez, Jesus E, Moreno-Bravo, Juan A, Madrigal, M Pilar, Martinez, Salvador, Puelles, Eduardo. 2015. Mesencephalic basolateral domain specification is dependent on Sonic Hedgehog. In Frontiers in neuroanatomy, 9, 12. doi:10.3389/fnana.2015.00012. https://pubmed.ncbi.nlm.nih.gov/25741244/