Introduction: 
 
Agenesis is one of the most common dental malformations, often affecting the frontal group of teeth of the upper jaw and premolar areas. Dental agenesis occurs when one or more teeth of temporary bite and/or permanent bite are missing during development [2]. The method of determining the type of agenesis is based on an assessment of the number of teeth missing during development: hypodontia is often used as a collective term for innately missing teeth, although it specifically describes the absence of one to six teeth, excluding the third molars. Oligodontia refers to the absence of more than six teeth, excluding the third molars, while anodontia is the complete inability of one or both dentitions to develop [1]. 
Despite the rapid development of new technologies, devices and methods in dentistry, currently there are only a few options for the treatment of missing teeth — this is prosthetics on implants or the use of removable and non-removable orthopedic structures. However, recently the scientific society has been actively conducting research on this topic, since dental agenesis entails significant functional, aesthetic and psychosocial problems in patients. 
The topic of this work is important and relevant in the field of medical research and biotechnology. Oral diseases remain one of the most common medical problems in the world. Existing methods of replacing lost teeth, such as implants and orthopedic structures, have their limitations and can cause complications. Research in the field of dental cultivation can provide more effective and safe alternatives that take into account the individual needs of patients. 
The purpose of this work is to study the processes associated with the growth and development of teeth in humans and animals in order to better understand the molecular and cellular mechanisms underlying them. 

The main part:

Since the development of teeth is under a certain degree of genetic control, it follows that agenesis is also influenced by genes. For this reason, many studies have focused on identifying specific genes that are involved in the regulation of dental development. Past research has mainly relied on family studies to identify these genetic variants. Studies of mutations in mice and cultured tissue explants have led to the expression of more than 200 genes involved in dental development, and have provided insight into inductive signaling and a hierarchy of transcription factors necessary for dental development [9]. In our work, we will consider only the uterine sensitivity-associated gene-1 (Usag-1), since many studies indicate its predominance in the process of dental agenesis [3,7]. 
A number of mutation simulations in mice allowed us to get ideas about the formation of “additional” teeth [6]. In mice, unlike humans, incisors and three molars are constantly erupting, which are separated by an area without tooth formation called a diastema. Several mechanisms have been proposed to explain the formation of “extra” teeth in mice [7]. Usag-1 is an antagonist of Bone morphogenetic protein (BMPs) [3]. Scientists have found that inhibition of apoptosis can lead to the sequential development of rudimentary maxillary incisors in mice without Usag-1 [7]. In addition, in mice with Usag-1 deficiency, it was found that increased BMP transmission prevents apoptosis, leading to the development of “additional” teeth [7,8]. In particular, studies show that specific interactions between BMP-7 and Usag-1 regulate the formation of “additional” rudimentary maxillary incisors [8]. 
In turn, with a deficiency of Runt-related transcription factor 2 (Runx2), on the contrary, there is a delay in the development of teeth, and this phenotype was compared with the phenotype of a patient carrying a unique missense mutation Arg131Cys Runx2, who had a congenital tooth missing. Runx2 is the main regulator of osteoblastogenesis, directs the transcription program necessary for bone formation through genetic and epigenetic mechanisms. The removal of Runx2 in mice leads to the absence of a mineralized skeleton, and a violation of the function of Runx2 causes bone defects in human disease - kleidocranial dysplasia [3,4,5].
Research results have shown that local use of Usag-1 contributed to the development of teeth in agenesis associated with Runx2 deficiency.  It was also found that delayed tooth formation was restored using Usag-1 [3]. 
The findings suggest that mice may be suitable as models for studying congenital dental agenesis in humans. 
It is also important to note the potential crosstalk between Usag-1 and Runx2 during tooth development. The study identified three interesting phenomena with both zero Usag-1 and Runx2 in mice: the prevalence of “additional” teeth was lower than in mice with zero Usag-1; tooth development progressed further than in mice with zero Runx2; and the frequency of formation of molar rudiments was lower than in mice with zero Runx2. Therefore, it can be assumed that Runx2 and Usag-1 act in an antagonistic manner [10]. In the course of our discussion, we came to the conclusion that Usag-1-associated dental agenesis can develop in two states: with a deficiency of Runx2 or with an excess of Usag-1.
To investigate whether topical application of Usag−1 in cationized gelatin hydrogels can restore delayed tooth development in mice with Runx2 deficiency, transplantation of the mandibular rudiments of mice with Runx2 deficiency together with small interfering RNAs (miRNAs) contained in Usag-1 #304 and #903 was performed. In the absence of Usag-1 miRNA, flattening of explants and lack of growth of transplanted mandibles were observed. However, there was an increase in explants (42.3%) after topical application of Usag-1 #304 miRNA, but not Usag-1 #903 miRNA. Moreover, no mineralized hard tissues such as bone, dentin or enamel were found. In addition, histological examination of the growing mandibles treated with Usag-1 #304 miRNA did not reveal the structure of the teeth; however, odontogenic epithelial-like cells were observed, regularly arranged in the form of elongated rectangular cells with nuclear polarity. sqRT-PCR analysis showed that the genes encoding enamel-specific proteins, amelogenin and ameloblastin, were poorly expressed, and subsequent immunohistochemical examination of amelogenin confirmed local expression in odontogenic epithelial-like cells. These results demonstrated that topical application of Usag−1 #304 miRNA partially reversed the arrest of tooth development in mice with Runx2 deficiency. The results indicate that the method developed in this study demonstrates potential in the treatment of patients with congenital dental agenesis as a result of the Runx2 mutation [3]. 
If we consider dental agenesis as a consequence of an excess of Usag-1, it was found that Usag-1 and BMP-7 are expressed in the odontogenic epithelium, in the mesenchyma at the rudimentary stage and at the early stage of the dental sac. Usag-1 is a BMP antagonist and also modulates Wnt signaling. Also, a detailed analysis of mice with Usag-1 deficiency showed that an “additional” incisor developed on the lingual side of the permanent tooth, and it is believed that this tooth belongs to the “additional” generation of teeth [11, 12]. It was later found that the “additional” incisor in mice with a deficiency of lipoprotein receptor-related protein-4 (Lrp4) has the same origin as the “additional” incisor with a deficiency of Usag-1 [13]. Based on this, we can assume that Usag-1 inhibits Wnt and BMP signals through direct binding to BMP and the Wnt coreceptor [14]. 
To confirm this assumption, a study was conducted in which Usag-1 antibodies were systemically injected into pregnant mice with ectodysplasin A1 (EDA1) deficiency.  Usag-1 neutralizing antibodies #16, #37, #48 and #57 cured mandibular molar hypodontia in mice with EDA1 deficiency compared to control mice (without the use of antibodies). It is worth noting that mice injected with Usag-1 neutralizing antibodies #12, #16 or #48 had low fertility and survival rates. 
Finally, to confirm that the activity neutralizing Usag-1 affects the transmission of BMP signals for the formation of a whole tooth, the study systematically injected antibody #37 to postnatal ferrets that had both milk and permanent teeth. The formation of “additional” teeth in the upper jaw was observed, although a five-fold higher concentration was required, three consecutive injections of antibody #37 and immunosuppression. The “additional” tooth had a shape similar to an ordinary permanent incisor located on the lingual side of the permanent teeth, while at the same time having a shorter root [14]. Unexpectedly, Usag-1-neutralizing antibody #57 also induced the formation of “additional” teeth in the upper jaw at a high rate and in a dose-dependent manner. However, they had fused molars.  
Both antibodies neutralized the antagonistic function of BMP signaling, at least in vitro. These results indicate that BMP signaling is necessary to determine the number of teeth in mice. In addition, systemic administration of a neutralizing antibody can lead to the formation of an entire tooth [14].  
However, based on these results, the involvement of Wnt signaling cannot be ruled out, since several mice were not born or did not survive. Thus, further experiments are needed, such as epitope binning involving more Usag–1 neutralizing antibodies and detailed analysis of recombinant epitopes of the Usag-1 protein [14]. 

Conclusion:
 
In the course of this work, we came to the conclusion that growing teeth is not a myth, but the reality of modern dentistry. Many current studies are aimed at solving the problem of dental agenesis, and the use of gene technologies is the most relevant branch in this matter. Japanese scientists have scheduled the start of clinical trials for the summer of 2024, and if safety is confirmed, they plan to make this therapy available to all patients no earlier than 2030. Therefore, we can confidently assume that in the near future these technologies will be used to treat agenesis in humans.