# The Chronological Trigger: The Orchestra Between Homeobox Genes and the Circadian Clock During Development **Authors:** Joice de Faria Poloni, Bruno César Feltes PMC · DOI: 10.1111/boc.70027 · 2025-07-25 ## TL;DR This paper explores how homeobox genes and the circadian clock interact during development, highlighting their roles in regulating cellular differentiation and embryonic structure formation. ## Contribution The paper provides a critical review and new perspectives on the crosstalk between homeobox genes and circadian regulation in development. ## Key findings - Homeobox genes and circadian rhythms are interconnected in regulating embryonic development. - The interplay influences cellular differentiation and tissue formation. - New insights into the regulatory mechanisms of development are presented. ## Abstract As master regulators of embryonic development, regulating homeobox genes is fundamental for developmental biology. Despite the growth of multiple topics regarding fine‐tuning homeobox gene expression, the discussion on how the circadian rhythm affects their control and vice‐versa still needs to be improved. Due to the intrinsic importance of the circadian clock and its impact on several molecular mechanisms, including development and pregnancy, the interplay between this mechanism and homeobox genes becomes a meaningful discussion. This work aims to review and critically discuss the crosstalk between homeobox genes and circadian regulation in multiple organisms, focusing on differentiation and developmental mechanisms. A considerable focus is given to new perspectives on the topic. Homeobox genes associated with the circadian rhythm and the development of specific tissues, playing crucial roles in regulating cellular differentiation and the formation of structures during embryonic development. ## Full-text entities - **Genes:** Hoxa11 (homeobox A11) [NCBI Gene 15396] {aka Hox-1.9, Hoxa-11}, Tph1 (tryptophan hydroxylase 1) [NCBI Gene 21990] {aka Tph}, Lhx9 (LIM homeobox protein 9) [NCBI Gene 16876] {aka 3110009O07Rik, LH2B}, Crx (cone-rod homeobox) [NCBI Gene 12951] {aka Crx1}, Six6 (sine oculis-related homeobox 6) [NCBI Gene 20476] {aka Optx2, Six9}, Csnk1a1 (casein kinase 1, alpha 1) [NCBI Gene 93687] {aka 2610208K14Rik, 4632404G05Rik, 5430427P18Rik, CK1a, Csnk1a}, Zfhx3 (zinc finger homeobox 3) [NCBI Gene 11906] {aka A230102L03Rik, Atbf1, Sci, WBP9, mKIAA4228}, Hoxc4 (homeobox C4) [NCBI Gene 15423] {aka Hox-3.5}, Aanat (arylalkylamine N-acetyltransferase) [NCBI Gene 11298] {aka AA-NAT, Nat-2, Nat4, Snat}, Otx2 (orthodenticle homeobox 2) [NCBI Gene 18424] {aka E130306E05Rik}, Bsx (brain specific homeobox) [NCBI Gene 244813] {aka Bsx1a, Bsx1b}, Gucy2d (guanylate cyclase 2d) [NCBI Gene 14918], crx (cone-rod homeobox) [NCBI Gene 81881], lhx2b (LIM homeobox 2b) [NCBI Gene 791744] {aka bel, lhx2, zgc:152707}, Lhx2 (LIM homeobox protein 2) [NCBI Gene 16870] {aka LH2A, Lh-2, Lim2, ap, apterous}, Sag (S-antigen, retina and pineal gland (arrestin)) [NCBI Gene 20215] {aka A930001K18Rik, Arr1, Irbp, arrestin}, Pde6b (phosphodiesterase 6B, cGMP, rod receptor, beta polypeptide) [NCBI Gene 18587] {aka Pdeb, r, rd, rd-1, rd1, rd10}, Ppia-ps1 (peptidylprolyl isomerase A, pseudogene 1) [NCBI Gene 110998] {aka Cyc, Ppia-ps}, Pax6 (paired box 6) [NCBI Gene 18508] {aka 1500038E17Rik, AEY11, Dey, Gsfaey11, Pax-6, Sey}, Rax (retina and anterior neural fold homeobox) [NCBI Gene 19434] {aka 7530406A22Rik, E130303K03Rik, Rx, ey-1, ey1}, Cry2 (cryptochrome circadian regulator 2) [NCBI Gene 12953] {aka D130054K12Rik}, Lhx4 (LIM homeobox protein 4) [NCBI Gene 16872] {aka A330062J17Rik, Gsh-4, Gsh4}, tph1a (tryptophan hydroxylase 1 (tryptophan 5-monooxygenase) a) [NCBI Gene 352943] {aka tph, tph1, tph1-1, tphD1}, Thim (thymoma insertional mutation) [NCBI Gene 117216] {aka Tim-1}, Clock (clock circadian regulator) [NCBI Gene 12753] {aka 5330400M04Rik, KAT13D}, LHX4 (LIM homeobox 4) [NCBI Gene 89884] {aka CPHD4}, Hoxa10 (homeobox A10) [NCBI Gene 15395] {aka Hox-1.8, Hoxa-10}, Per2 (period circadian clock 2) [NCBI Gene 18627] {aka mKIAA0347, mPer2}, Csnk1d (casein kinase 1, delta) [NCBI Gene 104318] {aka 1200006A05Rik, D930010H05Rik}, Bmal1 (basic helix-loop-helix ARNT like 1) [NCBI Gene 11865] {aka Arnt3, Arntl, BMAL1b, MOP3, bHLHe5, bmal1b'}, scro (scarecrow) [NCBI Gene 3355151] {aka 80Fb, CG17594, CG17595, CG18452, Dmel\CG17594, l(3)80Fb}, Six3 (sine oculis-related homeobox 3) [NCBI Gene 20473] {aka E130112M24Rik, Six3a, Six3alpha, Six3b, Six3beta}, LOC100518330 (serotonin N-acetyltransferase) [NCBI Gene 100518330] {aka AANAT}, Per1 (period circadian clock 1) [NCBI Gene 18626] {aka Hftm, Per, m-rigui, mPer1}, Csnk1e (casein kinase 1, epsilon) [NCBI Gene 27373] {aka CK1epsilon, CKIe, KC1epsilon, tau}, Grk1 (G protein-coupled receptor kinase 1) [NCBI Gene 24013] {aka Gprk1, Rhok, Rk}, Cry1 (cryptochrome circadian regulator 1) [NCBI Gene 12952] {aka Phll1}, Rcvrn (recoverin) [NCBI Gene 19674] {aka CAR, S-modulin}, Tim (translocation induced circling mutation) [NCBI Gene 107698], Gnat2 (G protein subunit alpha transducin 2) [NCBI Gene 14686] {aka Gnat-2, Gt-2, Hg1d, Tcalpha}, Vax1 (ventral anterior homeobox 1) [NCBI Gene 22326], Pax4 (paired box 4) [NCBI Gene 18506] {aka Pax-4}, bsx (brain-specific homeobox) [NCBI Gene 573364], Cngb1 (cyclic nucleotide gated channel beta 1) [NCBI Gene 333329] {aka CNG-4, CNG4, Cngb1b, Garp2, Gm1959}, LHX1 (LIM homeobox 1) [NCBI Gene 100513681], Asmt (acetylserotonin O-methyltransferase) [NCBI Gene 107626] {aka Hiomt}, aanat2 (arylalkylamine N-acetyltransferase 2) [NCBI Gene 30685] {aka AA-NAT}, Guca1b (guanylate cyclase activator 1B) [NCBI Gene 107477] {aka GCAP2}, otx5 (orthodenticle homolog 5) [NCBI Gene 353179] {aka cb828}, Mt2 (metallothionein 2) [NCBI Gene 17750] {aka MT-II, Mt-2}, Nr1d2 (nuclear receptor subfamily 1, group D, member 2) [NCBI Gene 353187] {aka RVR, Rev-erb}, Nr1d1 (nuclear receptor subfamily 1, group D, member 1) [NCBI Gene 217166] {aka A530070C09Rik}, ISL1 (ISL LIM homeobox 1) [NCBI Gene 100511417], Slc24a1 (solute carrier family 24 (sodium/potassium/calcium exchanger), member 1) [NCBI Gene 214111] - **Diseases:** Alzheimer's Disease (MESH:D000544), DD (MESH:C536170), neurological disorders (MESH:D009461), brain injuries (MESH:D001930), cancer (MESH:D009369), Fragile X Syndrome (MESH:D005600), allergies (MESH:D004342), infant colic (MESH:D003085), cataracts (MESH:D002386), dementia (MESH:D003704), vitamin deficiency (MESH:D014802), carcinogenesis (MESH:D063646), arrhythmic (OMIM:212500), embryonic lethality (MESH:D020964), cytotoxic (MESH:D064420), sleep disorders (MESH:D012893), obese (MESH:D009765), multiple sclerosis (MESH:D009103), respiratory diseases (MESH:D012140), melatonin deficiency (MESH:D007153) - **Chemicals:** tamoxifen (MESH:D013629), dopamine (MESH:D004298), tryptophan (MESH:D014364), estradiol (MESH:D004958), N-acetylserotonin (MESH:C006389), Melatonin (MESH:D008550), retinoids (MESH:D012176), 5-hydroxytryptophan (MESH:D006916), GABA (MESH:D005680), Cipolla (-), cGMP (MESH:D006152), serotonin (MESH:D012701), norepinephrine (MESH:D009638), RA (MESH:D014212) - **Species:** Mus musculus (house mouse, species) [taxon 10090], Actinopterygii (fishes, superclass) [taxon 7898], Rattus norvegicus (brown rat, species) [taxon 10116], Caenorhabditis elegans (species) [taxon 6239], Bos taurus (bovine, species) [taxon 9913], Capra hircus (domestic goat, species) [taxon 9925], Sus scrofa (pig, species) [taxon 9823], Xenopus laevis (African clawed frog, species) [taxon 8355], Drosophila melanogaster (fruit fly, species) [taxon 7227], Homo sapiens (human, species) [taxon 9606], Danio rerio (leopard danio, species) [taxon 7955], Melanogaster (genus) [taxon 80614], Sparus aurata (gilthead bream, species) [taxon 8175] - **Cell lines:** C57BL/6 — Mus musculus (Mouse), Transformed cell line (CVCL_C0MU) ## Figures 4 figures with captions in the complete paper: https://tomesphere.com/paper/PMC12292753/full.md --- Source: https://tomesphere.com/paper/PMC12292753